Immune Mediated Disorders - Oral Pathology PDF

TERM IIIMMUNE MEDIATED DISORDERS Prof. Dr. Sofia Ali Syed Head Department of Oral Pathology DIKIOHS, DUHS Learning Objectives By the end of lecture 2nd year BDS students will be able to Describe the etiopathology, clinical features and microscopic features of immune mediated diseases Differen...

TERM IIIMMUNE MEDIATED DISORDERS Prof. Dr. Sofia Ali Syed Head Department of Oral Pathology DIKIOHS, DUHS Learning Objectives By the end of lecture 2nd year BDS students will be able to Describe the etiopathology, clinical features and microscopic features of immune mediated diseases Differentiate immune mediated diseases on the basis of clinical features, histopathology and immunofluorescence RECURRENT APHTHOUS STOMATITIS (RAS) Common disease in humans. Most common condition affecting the mucosal soft tissue 3 types Minor Major Herpetiform APTHOUS MINORRECURRENT APHTHOUS STOMATITIS (RAS) Most common type Painful, small, superficial ulcers of the oral gland-bearing mucosa that occur episodically in clusters of 1-5 lesions. APTHOUS MINORRECURRENT APHTHOUS STOMATITIS (RAS) Clinical Features: Peak age of onset: 10 -19 years Number of lesions: 1-5 , < 5 in number, episodically in clusters Location: Mostly mucosal surfaces of the lips, posterior soft palate, and anterior fauces Shape: Individual lesions : round or elliptical (if located in a crease or fold of the tissue) Size: 0.5 mm to 1.0 cm in diameter and shallow with sharp crateriform edges Base of ulcer: Whitish-yellow bases Edges: Sharp crateriform, erythematous halo or flares on surrounding mucosa. Healing: 10-14 days new lesions may continually appear for : 3 - 4 week period Painful, small, superficial ulcers The pain occur for few days and continues to intensify for 7 to 10 more days before finally healing in 10 to 14 days APTHOUS MINORRECURRENT APHTHOUS STOMATITIS (RAS) APTHOUS MINORRECURRENT APHTHOUS STOMATITIS (RAS) Histopathology Pre-ulcerative stage Mild infiltrate of T4 helper and lymphocytes in perivascular locations of the submucosal tissue. Ulcerative stage Epithelium: T cells within the epithelium 🡪 vacuolization and necrosis🡪 disintegration and ulceration🡪 ulcer surface Ulcer surface: Fibrinopurulent exudate over granulation tissue + prominent neutrophils, macrophages, and plasma cells Connective tissue: Dense infiltrates of T8 suppressor and cytotoxin. The perivascular infiltrates are found more deeply in the submucosal tissue Normal healing: Epithelium migrates over fibrous tissue. During this final phase the predominant lymphocyte subset reverts back to a T4 population APTHOUS MINORRECURRENT APHTHOUS STOMATITIS (RAS) Loss of epithelium ? * * Can you label it ? APTHOUS MINORRECURRENT APHTHOUS STOMATITIS (RAS) APTHOUS MAJORRECURRENT APHTHOUS STOMATITIS (RAS) One or two uncommon, large, superficial, painful ulcers; usually appear on the labial mucosa and soft palate. Second most-common form of RAS. It was previously referred to as “periadenitis mucosa necrotica recurrens,” reflecting the propensity of the lesions to occur over areas of mucosa containing a large number of minor salivary glands. APTHOUS MAJORRECURRENT APHTHOUS STOMATITIS (RAS) Clinical Features Size: Large, 5 mm to 20 mm or more Number: Fewer Site: Mucosa of the lips, posterior soft palate & anterior fauces area Edges: crateriform Depth: deeper than aphthous minor Duration: upto 6 weeks Intensity of pain: Severe, making eating difficult, particularly when lesions are located in the posterior aspect of mouth. Healing: occurs with scar formation & tissue contracture 🡪 unusual because most minor injuries heal without noticeable scar formation. APTHOUS MAJORRECURRENT APHTHOUS STOMATITIS (RAS) APTHOUS MAJORRECURRENT APHTHOUS STOMATITIS (RAS) Histopathology Ulcer surface: Fibrinopurulent exudate over granulation tissue Connective tissue: Extends deep into the underlying connective tissue Prominent lymphocytes in perivascular region APTHOUS MAJORRECURRENT APHTHOUS STOMATITIS (RAS) Rare or least common form of RAS multiple, small, diffuse, painful, superficial ulcers with episodes of long duration Location: both gland-bearing and keratinized mucosal surfaces. Number: multiple Size: 3 to 6 mm in diameter Shallow and crateriform HERPETIFORM ULCERRECURRENT APHTHOUS STOMATITIS (RAS) HERPETIFORM ULCERRECURRENT APHTHOUS STOMATITIS (RAS) Duration of episode: weeks to months, or several years. During prolonged attacks, individual lesions heal and new lesions continually reappear Misdiagnosed as primary herpes simplex infections: Closely resemble clinically (hence their name) Because the presence of lesions on the keratinizing mucosal surfaces is common in primary herpes infection too Symptom: severe pain HERPETIFORM ULCERRECURRENT APHTHOUS STOMATITIS (RAS) Histopathology Identical to aphthous minor. No scarring: because lesions 🡪 shallow with little connective tissue destruction Lab tests: Cytology smears do not show the cytopathic effects or the multinucleated cells found in the epithelium of viral infections Necessary to rule out primary herpetic stomatitis (viral cause) HERPETIFORM ULCERRECURRENT APHTHOUS STOMATITIS (RAS) BEHÇET SYNDROME A complex multisystem condition consisting of multiple oral, anogenital, and ocular aphthouslike lesions; frequently with arthralgia and associated central nervous system (CNS) Diagnosed by means of clinical criteria. Etiology Unknown. Immune factors, infectious agents Familial occurrences have been reported. More common in Japan and eastern Mediterranean countries where it is linked to those with the HLA-B5 alloantigen Pathogenesis: Vascular inflammation 🡪 tendency for venous thrombus. In 50% of the patients, circulating autoantibodies to oral mucous membrane are found. BEHÇET SYNDROME BEHÇET SYNDROME Clinical Features Age: young adults Gender: Males more severely afflicted than females Triad of oral, anogenital, and ocular aphthous like lesions 🡪 diagnosis of Behçet syndrome. Intraoral ulcers identical to aphthous minor ulcers Ocular symptoms: photophobia and uveitis Other common features: arthralgia (mainly of the ankles and knees), thrombophlebitis, CNS involvement, and macular and pustular skin lesions. In some, the skin is hypersensitive to minor scratches or other irritations. BEHÇET SYNDROME Histopathology Similar to aphthous minor, except that the vascular component is more prominent. Blood vessel walls exhibit infiltrates of inflammatory cells, resulting in a severe vasculitis that appears to destroy the vessel walls. Pathergy Test (read article given in the link below) http://dx.doi.org/10.1136/practneurol-2011-000072 BEHÇET SYNDROME LICHEN PLANUS (LP) A skin disease common within the oral cavity, where it appears as either white reticular, plaque, or erosive lesions with a prominent T-lymphocyte response in the immediate underlying connective tissue Lesions occur on both cutaneous and oral surfaces Cause is unknown, correlation with hepatitis C Clinical subtypes: Reticular Atrophic Hypertrophic, Erosive forms Initiating factors to activate regional cellular immune response: External antigen penetrate superficial cells to stimulate intraepithelial dendritic Langerhans cells Activation of T-lymphocyte response: Keratinocytes express intracellular adhesion molecules (ICAM) under the influence of epithelial chemotactic factors 🡪 stimulate CD4 and CD8 T-lymphocytes express integrin ligands and leukocyte function-associated antigen-1 (LFA-1) and are guided out of the submucosal vessels toward the basement membrane Keratinocytes also express major histocompatibility complex II (MHC-II) that bind T-lymphocyte receptor molecules🡪cytokines (perforins) 🡪apoptosis of the basilar and parabasilar epithelial cells LICHEN PLANUS PATHOGENESIS of LP (Lymphocytes) Basal cell lysis RETICULAR LP Clinical Features Easily diagnosed because of its unique and distinctive pattern Usually bilateral Site: mostly on buccal mucosa and the buccal vestibule than tongue and gingiva It is unusual for lesions to occur only on the hard or soft palates without involving most of the other oral mucosal surfaces. Raised, thin, white lines that connect in arcuate (bow) patterns, producing a lacework or reticular appearance against an erythematous background 🡪wickham’s striae Asymptomatic or complain of sore mouth RETICULAR LP Histopathology Epithelium Focal areas of epithelial hyperplasia Thick layer of orthokeratin or parakeratin surface The spinous cell layer may be thickened (acanthosis) with shortened and pointed (“saw-tooth”) rete pegs. The thickened areas are seen clinically as Wickham’s striae. Between Wickham’s striae, the epithelium is thinned (atrophic), with loss of rete peg formation Within the epithelium, rounded or ovoid amorphous eosinophilic bodies, referred to as Civatte bodies 🡪 apoptotic (dead) keratinocytes or other necrotic epithelial components that are transported to the connective tissue for phagocytosis. Connective tissue T lymphocytes 🡪 basement membrane 🡪 basilar and parabasilar layers RETICULAR LP RETICULAR LP RETICULAR LP ? ? ? ? ? ? EROSIVE LP Clinical Features Presentation: Mixture of erythematous and white pseudomembranous areas Junction between the erosive and the normal mucosa 🡪 a faint whitish tinge 🡪resembles radiating striae The whitish peripheral zone is most often present on the buccal mucosa and vestibule areas Symptoms: Sore mouth 🡪sensitive to hot/cold temp., spicy foods/alcoholic beverages Bland liquid diet in case of severe erosive During examination, touching the areas produces pain and bleeding. Hyperpigmentation (melanosis) in the healed areas EROSIVE LPDifferential diagnosis?? Histopathology Epithelium: Extensively thin Complete loss of rete peg formation Lymphocytes in basal, middle and upper levels Vacuolization and destruction of the basal cells Occasionally, subepithelial separation/cleft Basement membrane: Dense infiltrate of T lymphocytes that obscures the basement membrane Liquefaction of the basement membrane EROSIVE LP Histopathology Connective tissue: Often, the epithelium is lost, exposing the underlying connective tissue. The lymphocytes are confined to a narrow zone in the upper layers of the connective tissue. EROSIVE LP Dark blue dots Lymphocytes No rete pegs Connective tissue Epithelium capillaries Rete peg Hemosiderin, RBCs EROSIVE LP PLAQUE LP Clinical Features Presentation: white raised or flattened irregular area on the oral mucous membranes and is indistinguishable from other focal leukoplakias Location: mostly dorsal surface of tongue PLAQUE LPDifferential diagnosis? Histopathology Resembles striae of reticular LP but without atrophic areas Generalized hyperorthokeratosis or hyperparakeratosis combined with acanthosis There may be loss of rete pegs at the epithelial and connective tissue interface or alteration of their shape into a “saw-tooth” pattern. The basement membrane is noticeably thickened. The band of T lymphocytes present in the superficial connective tissue is less dense than in reticular LP, with only occasional cells found in the lower levels of the epithelium. PLAQUE LP ATROPHIC & BULLOUS LP Atrophic LP: Clinically as erythematous background of the reticular form. Site: mostly gingiva and buccal mucosa Bullous LP: A rare form of LP Large bullae ranging in size from 4 mm to 2 cm The bullae are of brief duration and rupture almost immediately; with the loss of the separated epithelium, the underlying connective tissue is exposed and the lesion becomes an erosive Site: Posterior buccal mucosa. LICHEN PLANUS Immunofluorescence Positive for fibrinogen along the basement membrane, with vertical extensions into the immediate underlying connective tissue. Negative for IgG, IgA and IgM antibodies Immunohistochemistry S-100 protein positive = increase in the Langerhans cells in the midlayers of the epithelium. LICHEN PLANUS Skin LP Purplish papules with white keratotic caps Itchy 🡪 linear lesions along the scratch mark Koebner phenomenon: skin lesion along the injury or irritation common in buccal mucosa along the occlusal line and commissure, lateral border of tongue and marginal gingiva Graft versus host disease Oral lesion is the first manifestation at times IDENTIFY THE FORM OF LICHEN PLANUS LICHENOID REACTIONS Lesions resembling erosive lichen planus, mainly on the buccal mucosa associated with the ingestion of some categories of medications and presence of other exogenous materials in the oral cavity Associated drugs include Systemically administered antibiotics Antihypertensives Gold compounds Diuretics Antimalarials Nonsteroidal antiinflammatory medications. LICHENOID REACTIONS Clinical features Site: posterior buccal mucosa. Symptom: painful Appearance: central erythematous area of erosion with a surrounding zone of radiating striae that gradually fade (sunburst appearance) LICHENOID REACTIONS Periphery: radiating white striae Central: erythematous area LICHENOID REACTIONS Histopathology Identical to LP and diagnosis is made when report indicate LP and disappears after drug is removed Occasionally show some microscopic features which are characteristic of oral discoid lupus erythematosus The histologic and immunologic changes caused by medications are not different from the reactions caused by the usual form of LP, occasional amalgam and gold contact lesions, and the LP-like eruptions in patients with GVHD. LICHENOID REACTIONS MUCOUS MEMBRANE PEMPHIGOID A desquamating condition of mucous membranes in which the autoimmune reaction occurs at the level of the basement membrane and commonly affects the gingiva before extending to other mucosal locations. The term pemphigoid is commonly used to indicate a desquamating or blistering disease in which epithelial separation takes place at the level of the basement membrane. Pathogenesis Autoantibodies are directed to protein targets (hemidesmosome) located in the lamina lucida of the basement membrane Name of target protein ? MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID Epithelial cells Connective tissue Basement membrane IgG antibodies hemidesmosomes Clinical Features Oral lesions: atrophic erythematous patches erosions, pseudomembranes, or collapsed blisters Site: most commonly on the attached gingiva and palatal mucosa. Minor irritation from routine tooth brushing/flossing 🡪 separation of the epithelium from the connective tissue 🡪blood-filled blisters or exposed connective tissue (desquamation) OR linear erosions along the free margins of the gingiva Under a denture 🡪tissue 🡪 generalized area of erythema and erosion. MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID Clinical Features Nikolsky sign: A clinical test that consists of rubbing or pushing on the tissue with a blunt instrument or gauze to determine if a blister forms in the next 1 to 2 minutes. The production of a blister, or bulla, indicates a positive sign. Site Oral lesions: Buccal mucosa, palate, and floor of the mouth may extend into the nasopharynx, larynx, and esophagus Ocular lesions: conjunctival erosions and can result in scarring, symblepharon, ankyloblepharon, corneal neovascularization, and serious loss of visual acuity Genital lesions may be present MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID Symblepharon: adhesions b/w conjunctiva & adjacent conjunctiva or cornea Ankyloblepharon: Partial or complete fusion of upper & lower eyelids MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID Corneal neovascularization: new vascular capillaries within and into the previously avascular corneal regions Histopathology Thinned epithelium that exhibits some attenuation of the rete pegs. Separation occurs at the basement membrane Connective tissue 🡪 infiltrated with lymphocytes, some plasma cells, and occasional eosinophils Prominent vasodilatation MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID Epithelium C.T Subepithelial Immunofluorescence Immunofluorescent deposit of IgG antibody and C3 that follows the basement membrane in a smooth and linear pattern MUCOUS MEMBRANE PEMPHIGOID MUCOUS MEMBRANE PEMPHIGOID PEMPHIGUS VULGARIS A desquamating condition of the oral mucosa and skin in which autoantibodies attack and destroy antigenic components of the desmosomes of the intermediate cells, producing epithelial separation above the basal cell layer. Etiology: Genetic predisposition Patients with specific, major histocompatibility antigens on their skin and to mucosal keratinocytes Drugs such as penicillamine, captopril, rifampin, penicillin phenobarbital Antigenic target: Desmosomal adhesion molecule, desmoglein 3 (a member of the cadherin family) When antibodies bind to the desmosomal complex Junctions lose adherent contact 🡪 acantholysis PEMPHIGUS VULGARIS Loss of adhesion occurs between the cells located in the zone above the basal cell layer 🡪suprabasilar bullous formation Other members of this disease group (pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus) represent milder forms and do not involve the oral cavity If untreated, PV can be a serious life-threatening disease Mortality is due mostly to a combination of advanced age, infection, and other complications of high-dose steroid treatment PEMPHIGUS VULGARIS Clinical Features Age: 40- to 60-yearold age group. Higher incidence in individuals of Mediterranean and Ashkenazic Jewish decent and those with specific histocompatibility antigens. Mainly affects the skin of the torso. In nearly 50% of patients with cutaneous PV, the oral lesions precede the presence of skin lesions, often by as much as 1 year. Other mucous membranes such as the nasopharynx, esophagus, vagina, and cervix can also be involved. Bullae are commonly present on skin but are rare on the oral mucosa. PEMPHIGUS VULGARIS PEMPHIGUS VULGARIS Multiple erosive lesions on buccal mucosa Dry , crusted lesion on skin Intraoral lesions: mostly soft palate. In intraoral locations the delicate surface layers are quickly lost 🡪 erythematous area that is sensitive to hot and cold temperatures, spicy foods, and alcoholic beverages. The free margin of the gingiva where chronic abrasion during toothbrushing is common, and the lateral borders of the tongue, where constant frictional activity occurs, will have larger and more intensely symptomatic erosive lesions. Both skin and mucosal tissue will have a positive Nikolsky sign. On the skin the individual lesions are produced by briefly appearing blisters that collapse with the formation of a brittle reddish crust (scab) PEMPHIGUS VULGARIS Multiple erosive lesions on soft palate Blister formation - positive Nikolsky sign PEMPHIGUS VULGARIS PARANEOPLASTIC PEMPHIGUS VULGARIS (PNP) A particular form of PV occurs in association with a preexisting occult or confirmed malignancy These patients have particularly painful mucosal lesions and papulosquamous eruptions of the skin that progress to blisters PNP occurs with some frequency in patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, thymoma, and some spindle cell tumors. PARANEOPLASTIC PEMPHIGUS VULGARIS (PNP) Histopathology Epithelium Normal thickness Normal rete peg formation. Acantholysis Tzanck cells: acantholytic cells lose their polygonal shape and become rounded with less cytoplasm visible around the nucleus Connective tissue: Mild inflammation PEMPHIGUS VULGARIS Acantholysis Desmosomes and extracellular proteins accomplish intercellular adhesion of oral keratinocytes. Within the desmosomes a group of transmembrane glycoproteins, known as desmogleins are present This loss of cellular adhesion (acantholysis) and the loss of the epithelial layer above the basilar layer results in a suprabasilar split. Early stages of PV: confined primarily to mucous membranes and the patient’s sera will contain circulating autoantibodies to desmoglein 3 Severe stages of PV is associated with skin lesions: patient’s sera will demonstrate autoantibodies to desmoglein 1 and 3. PEMPHIGUS VULGARIS PEMPHIGUS VULGARIS Intraepithelial or suprabasilar cleft Basal cell layer stratum spinosum Tzanck cells (acantholytic cells) Submucosa Immunofluorescence IgG antibody in a fishnet pattern 🡪attachment to the periphery of the cells in the lower portion of the spinous layer of the epithelium Patients with PNP, in addition to having suprabasilar acantholysis, may exhibit a lichenoid tissue reaction. The immunoreactants, IgG and complement, can be observed within the desmosomes (targeting the desmoplakin proteins) and the BMZ. PEMPHIGUS VULGARIS PEMPHIGUS VULGARIS EPIDERMOLYSIS BULLOSA A generalized desquamating condition of the skin and mucosa with associated scarring, contractures, and dental defects that occur in three main hereditary forms in children and one acquired form in adults. Epidermolysis bullosa (EB) is an encompassing term for a large group of clinically similar disease processes that have in common the separation of the epithelium from the underlying connective tissue and the formation of large blisters that frequently result in extensive and often immobilizing scar formation Types of Epidermolysis Bullosa Four basic types exist, each of which have multiple subtypes. Three of the types have hereditary patterns, and one is acquired in later life. Epidermolysis bullosa simplex (EBS) Cytolysis of the basal or intermediate cell layer (epidermolytic type) 🡪 intraepithelial cleft 2. Junctional epidermolysis bullosa (JEB): Cleft within the lamina lucida basement membrane at the level of the anchoring filaments EPIDERMOLYSIS BULLOSA 3. Dystrophic epidermolysis bullosa (DEB) Cleavage at the level of the type VII collagen-anchoring fibrils located beneath the lamina densa of the basement membrane where they extend into the dermis (dermolytic type) 4. Epidermolysis bullosa acquisita (EBA): Autoimmune origin: detectable IgG (and sometimes IgA) autoantibodies to type VII collagen is found EPIDERMOLYSIS BULLOSA In skin and mucosa, anchoring fibrils composed of type VII collagen are important constituents of the complex adherence system of epithelium to dermis. They attach the lamina densa portion of the basement membrane to the underlying dermis. The attachment of autoantibodies to type VII collagen triggers a complement-mediated inflammatory reaction that can result in severe damage to the anchoring fibrils. EPIDERMOLYSIS BULLOSA Mild form of EB Autosomal dominant pattern Appears during infancy, improving significantly by puberty. Sites: prone to friction or trauma 🡪 hands, feet, neck, and knees and elbows Mild intraoral blisters EPIDERMOLYSIS BULLOSA SIMPLEX JUNCTIONAL EPIDERMOLYSIS BULLOSA Severe form of EB Autosomal recessive trait. Hemorrhagic blisters Loss of nails Large blisters of the face, trunk, and extremities Generalized scarring and atrophy Intraoral lesions: Palate: large, fragile, hemorrhagic blisters Perioral and perinasal: crusted, granular, hemorrhagic lesions Teeth: hypoplastic and severely pitted enamel that rapidly develops caries. JUNCTIONAL EPIDERMOLYSIS BULLOSA DYSTROPHIC EPIDERMOLYSIS BULLOSA Both autosomal dominant and a recessive form Recessive phenotype 🡪 most severe forms Lesions are apparent at birth Sites: pressure areas 🡪 occiput, back, elbows, buttocks, and fingers Bullae rupture 🡪 painful ulcers 🡪 heal with large and deep scars 🡪 contracture 🡪 loss of mobility and claw like hands Fingernails and toenails are seldom present in adolescents and adults. Maybe marked skin depigmentation and deficient hair. Oral lesions: Blistering and scarring around the oral cavity 🡪 diminished opening, ankyloglossia and loss of vestibular sulci 🡪 difficulty in providing dental treatment Attempts at maintaining normal oral hygiene generate more blister formation Delayed eruption of teeth Enamel hypoplasia with rapid caries DYSTROPHIC EPIDERMOLYSIS BULLOSA DYSTROPHIC EPIDERMOLYSIS BULLOSA ACQUIRED EPIDERMOLYSIS BULLOSA Nonhereditary form of EB Manifested in adulthood Association: Multiple myeloma Diabetes mellitus Amyloidosis Tuberculosis Inflammatory bowel disease (particularly Crohn disease). Site: Trauma- or friction-induced blisters on Knees Elbows Dorsal side of the hands and feet Lesions heal with scars and milia Loss of nails and alopecia Intraoral blisters 🡪 scarring and a diminished oral opening 🡪 deterioration of oral hygiene, high caries rate, and periodontal disease ACQUIRED EPIDERMOLYSIS BULLOSA Histopathology Epidermolysis bullosa simplex: suprabasilar cleft In the remaining types of EB: subepithelial clefting EPIDERMOLYSIS BULLOSA Identify the cleft & also label the structures ERYTHEMA MULTIFORME A widespread hypersensitivity reaction that occurs in mild and severe forms and produces tissue reactions centered on the superficial vessels of the skin and mucous membranes; usually occurs in patients as the result of an inciting agent. Etiology: Common precipitating factors are Infections such as herpes simplex, mycoplasma pneumonia, & histoplasmosis Drugs (most commonly sulfas, penicillin, dilantin, barbiturates, iodines, and salicylates) GI conditions (notably Crohn disease and ulcerative colitis) Other conditions such as malignancy, radiation therapy, and recent vaccination Many cases exist in which a precipitating factor cannot be identified. ERYTHEMA MULTIFORME Pathogenesis Unknown Circulating immune-related complexes after infections and medications Targets surface epithelium and the walls of blood vessels in the lamina propria Antibodies against an exogenous antigen 🡪 AgAb complex 🡪 circulates in the blood 🡪 filtered in blood vessels walls 🡪 vasculitis 🡪 thrombosis and ischemic necrosis. The resulting skin and mucosal reactions range from a mild erythema to widespread necrosis with sloughing of the epithelial layer, depending on the intensity of the immune response to the antigen ERYTHEMA MULTIFORME The immunopathogenesis of EM is linked to exogenous rather than endogenous antigen. Pharmacologic agents such as sulfa drugs or herpes virus antigens form circulating immune complexes that filter into vascular basement membranes in skin and mucosa. These components bind complement and initiate a vasculitis with thrombosis and ischemic necrosis of the overlying epithelium. ERYTHEMA MULTIFORME Clinical Features Clinical types: EM minor Chronic EM minor EM major Types of EM major Steven Johnson syndrome Toxic epidermolysis necrosis ERYTHEMA MULTIFORME Site: skin; 25% oral mucosa Prodromic period: 3 to 7 days Severe headache, fever, and malaise Followed by emergence of focal or diffuse areas of erythema 🡪 classic skin lesion referred to as a “target,” “bull’s eye,” or “iris” lesion ERYTHEMA MULTIFORME MINOR Target lesion Appearance of a concentric erythematous patch that contains a peripheral thin zone of pallor and is surrounded by one or more additional thin erythematous rings. Early stages: Center of the ring = papule or small bulla that collapses🡪 transient central erosion that quickly heals and returns to normal, which then produces the center of the “bull’s eye” Few millimeters to many centimeters Distributed mostly on the flexor surfaces of the extremities Trunk and facial surfaces are less frequently involved. ERYTHEMA MULTIFORME MINOR ERYTHEMA MULTIFORME MINOR Central blister Pallor zone Erythematous ring ERYTHEMA MULTIFORME MINOR ERYTHEMA MULTIFORME MINOR Mildest form of EM. Skin lesions: smaller in size and of shorter duration and distribution with duration of 1 or more years Appearance of the lesions is similar to that of a disseminated viral eruption Individual lesions will disappear rather than developing into large “target” lesions. Oral lesions: similar in both forms of EM minor Vary from focal erosions resembling aphthous ulcers to more diffuse painful areas of erythema or erosions CHRONIC ERYTHEMA MULTIFORME MINOR Acute form of the disease Severe involvement of both the skin and mucous membranes. Target lesion Large bullae of both the muous membranes and skin and occasionally a positive Nikolsky sign are characteristic of this form. Bullae quickly collapse, producing whitish pseudomembranes on the mucosa and dark-red, crusted lesions on the dry skin surfaces especially on lips and eyes because after sleeping, patients are often unable to open their eyes or part their lips because of the dry encrustations. ERYTHEMA MULTIFORME MAJOR ERYTHEMA MULTIFORME MAJOR STEVEN JOHNSON SYNDROME (SJS) Acute form Young patients Widespread epidermal detachment involves 10% or less of the total body skin area Mucosal lesions: mouth, eyes, esophagus, and genitalia. Oral lesions: sloughing and very painful Eye lesions: may lead to scarring and partial blindness ERYTHEMA MULTIFORME MAJOR STEVEN JOHNSON SYNDROME (SJS) TOXIC EPIDERMOLYSIS NECROSIS Extremely severe form Fatal in 30% to 35% of patients. Large sheets of skin become necrotic and slough, exposing denuded connective tissue 🡪 massive loss of electrolytes and widespread infection The skin areas clinically resemble severe burns caused by scalding water Oral lesions 🡪 similar to SJS but are even more diffuse and widespread ERYTHEMA MULTIFORME MAJOR TOXIC EPIDERMOLYSIS NECROSIS Histopathology Epithelium: Intercellular and intracellular edema🡪pooling of an eosinophilic amorphous coagulum 🡪 keratin mucopolysaccharide dystrophy Focal microvesicle formation Mononuclear and polymorphonuclear cells into all layers of the epithelium Acanthosis Irregular elongation of rete pegs Connective tissue: Diffuse infiltrate of mixed mononuclear cells of the upper portion of the lamina propria Vasodilatation of blood vessels with marked connective tissue edema and a tendency for interstitial transudate pooling often results in large zones of separation at the basement membrane level. ERYTHEMA MULTIFORME ERYTHEMA MULTIFORME ERYTHEMA MULTIFORME Connective tissue Lymphocyte in rete pegs/epithelium ERYTHEMA MULTIFORME Immunofluorescence: Immunofluorescent stains 🡪 negative for antigen and antibody reactions Mononuclear cells🡪 perivascular infiltrate, deep in the lamina propria, and within the muscle layers Immunofluorescence testing reveals that the deep perivasculitis is positive for IgM and C3 Tissue Diagnosis of Erosive Diseases of the mucosa LUPUS ERYTHEMATOSUS A chronic inflammatory condition of the skin, connective tissue, and specific internal organs that has associated circulating autoantibodies to DNA and other nuclear and RNA proteins Circular whitish bucco-mucosal lesions and erythematous rashes of the sun-exposed skin are common Etiology: It still not fully understood but is considered to be multifactorial, triggered by a combination of genetic, environmental, and hormonal factors Environmental factors: Viral infection Ultraviolet (UV) light Drugs. LUPUS ERYTHEMATOSUS Discoid lupus erythematosus (DLE) Chronic, mildest form Confined to the sun-exposed skin of the face, scalp, and ears but also involves the oral mucosa Subacute cutaneous lupus erythematosus (SCLE) Subacute, intermediate form More widespread, affects the head and neck,upper trunk, and extensor surfaces of the arms Systemic lupus erythematosus (SLE) Acute, severe form Primarily involves the organs, especially the kidneys Rashes occur periodically on the upper trunk and face TYPES OF LUPUS ERYTHEMATOSUS Pathogenesis Altered immune system is responsible for the deleterious changes that take place within the basal cells, basement membrane, collagen, and vascular tissue Autoantibodies to nuclear DNA (antinuclear antibodies [ANAs]) ribonuclear protein antigens, and cytoplasmic and surface antigens are present in the blood. The serology also notes an increase in B-cell function and circulating autoantibodies that exhibit cross-reactivity with antigenic determinants of multiple tissues. LUPUS ERYTHEMATOSUS Pathogenesis Increase in cell death of lymphocytes🡪nucleosomes 🡪 act as foreign antigen🡪 stimulate B lymphocytes 🡪 antibody to foreign antigens🡪 cross-react with normal cellular contents🡪antigen-antibody immune complexes🡪 deposited throughout body, especially in the kidneys (lupus nephritis) and the blood vessel walls (vasculitis) of all organs, including the skin. Genetic predisposition Viral agent UV light can also cause disease but pathogenesis is unknown LUPUS ERYTHEMATOSUS Systemic Lupus Erythematosus (SLE) Common form with highest morbidity Damage to the glomeruli can be severe. Widespread arthritis and arthralgia Heart and lung involvement Anemia and bone marrow depression Diffuse vasculitis and skin rashes, most notably the “butterfly rash” over the malar areas of the face Fatigue, malaise, fever, and psychosis. Affects females usually during the childbearing years. Oral lesions are less common in SLE but more symptomatic and involves more intraoral structures Systemic Lupus Erythematosus (SLE) Subacute Cutaneous Lupus Erythematosus Affects the skin of the upper parts of the body, with systemic and musculoskeletal components mildly involved Chronic skin rashes are present for months but eventually heal Muscle and joint stiffness, malaise, and fatigue are common Circulating ANAs and SS-A/Ro antibodies to cytoplasmic constituents are found Discoid Lupus Erythematosus Cutaneous lesions: Face, scalp, external ears Scalp involvement with hair loss (alopecia) Erythematous plaques with a thick adherent scale that occludes hair follicles are seen on skin Hypopigmented atrophic areas with erythematous raised borders that may be present for years Occasionally oral mucosa: Chronic erythema that is sensitive, often with a burning sensation LUPUS ERYTHEMATOSUS Clinical Features Oral mucosal lesion appear as annular leukoplakic areas, erythematous erosions, or chronic ulcerations Chronic oral lesion appear as leukoplakic patch that does not ulcerate and may have few symptoms Although oral lesions are occasionally the first physical sign of LE, oral and skin lesions appear simultaneously in most cases. LUPUS ERYTHEMATOSUS Histopathology Target antigen appears in the basal and parabasal layers Epithelial atrophy Degeneration of epithelial cells Increase in thickness of the basement membrane Loss of rete peg Concentrations of lymphocytes in the immediate underlying lamina propria, germinal centers and perivascular area In the more chronic lesions the presence of hyperorthokeratosis and surface depressions containing keratin (keratin plugging) suggests that a lesion is LE rather than LP. LUPUS ERYTHEMATOSUS LUPUS ERYTHEMATOSUS Label the diagram Direct immunofluorescence: Granular linear pattern to the IgA, IgM, and IgG immunoglobulins; fibrinogen; and C3. Such pattern help to distinguish LE from LP LUPUS ERYTHEMATOSUS OROFACIAL GRANULOMATOSIS Clinicopathologic term Describing a group of oral conditions of varying causes, all with a similar microscopic feature of noncaseating granulomas Combination of oral manifestations of Crohn disease, the localized oral entity of cheilitis granulomatosis, and a collection of pathophysiologic findings called Melkersson-Rosenthal syndrome (MRS). In some cases, patients with orofacial granulomatosis will develop the typical bowel symptoms of Crohn disease in the ensuing months to years. Others will eventually be found to have sarcoidosis, a reaction to an infection or foreign material or a hereditary predisposition for granulomas such as chronic granulomatous disease (CGD) of childhood. The use of the umbrella term of orofacial granulomatosis is valuable, because it immediately places the initial findings in a category and indicates the need to search for the specific underlying or local cause of the condition OROFACIAL GRANULOMATOSIS ORAL CROHN DISEASE Crohn disease is a chronic inflammatory disease of the GI tract Site: any location from the mouth to the anus. In 90% of cases, the terminal ileum is involved alone or in combination with the ascending colon. When located in the large and small bowel area, it consists of small abscess and noncaseating granulomas that may, with time, extend throughout the bowel wall and even into the serosa. The disease characteristically has large skip areas of normal tissue between areas of abscesses, granulomas, fibrosis, and fistulas. Clinical Features Rarely in oral cavity Buccal mucosa : cobble stone appearance Vestibule: linear hyperplastic folds with ulcers Lips: diffusely swollen and indurated Gingiva and alveolar mucosa: granular and erythematous swelling Palate: multiple apthous ulcer The oral lesions may become present months to years before abdominal symptoms occur or the diagnosis of Crohn disease is made ORAL CROHN DISEASE ORAL CROHN DISEASE ORAL CROHN DISEASE ORAL CROHN DISEASE  Histopathology Non caseating granulomas Aphthous like ulcerations. (Small and multiple or large and deep) combinations of both tissue types may be found ORAL CROHN DISEASE SARCOIDOSIS A chronic disease affecting the skin, mucosa, salivary glands, lungs, and other organs; consists of multiple noncaseating epithelioid granulomas and fibrosis of adjacent tissue. Etiology Idiopathic Ethnicity and hormonal factors Major histocompatibility antigen status such as HLA-B5, -B7, -B8, HLA-A9, HLA-Cw7, and HLA-DR3 types Allergic to antigens found in some infectious agents such as mumps, tuberculosis, and candida Reduced levels of circulating T lymphocytes Altered CD4/CD8 ratios Elevated levels of serum lysozymes & serum angiotensin-converting enzymes SARCOIDOSIS Clinical Features Ethnicity: common in blacks Age: in America – at 40, in Europe - older age Symptom: lack of energy and difficulty in breathing. The lungs appear to be initially involved with extension through the lymphatics to the hilar and mediastinal lymph nodes. Skin lesions: multiple erythematous nodules Oral lesions : Diffuse submucosal enlargements or focal firm nodules Symptomless Site: lips, tongue, buccal mucosa, gingiva, hard and soft palate and floor of the mouth. SARCOIDOSIS Clinical Features Salivary gland: swelling of the parotids or submandibular glands, or both Lymph node; enlargement of head and neck along with lesions present in and around the nasal passages. Eye lesion: uveal tract A combination of lesions of the uveal tract, parotid gland, and seventh cranial nerve has been described as Heerfordt syndrome (uveoparotid fever). SARCOIDOSIS SARCOIDOSIS SARCOIDOSIS Histopathology Granuloma in nodular pattern: epithelioid cells multinucleated giant cells Lack caseous necrosis b. Periphery of each granuloma: cellular fibrous connective tissue Nuclei of multinucleated giant cells are present in ring shape Asteroid bodies: stellate shaped structure present in multinucleated giant cells SARCOIDOSIS SARCOIDOSIS Asteroid bodies Granuloma - nodular pattern Fibrous connective tissue Low power Multinucleated giant cell High power Class Assignment Label the diagram & write differential diagnosis DISCUSSION Name the ulcers which are preceded by vesicle or bulla Name the ulcers which are not preceded by vesicle or bulla Enlist the diseases causing desquamative gingivitis REFERENCE Contemporary Oral Pathology 2nd edition Article reading Recurrent aphthous stomatitis https://doi.org/10.1111/j.1600-0714.2012.01134.x Pemphigus vulgaris and bullous pemphigoid https://doi.org/10.5826%2Fdpc.1003a50 Oral lichen planus to oral lichenoid lesions: Evolution or revolution https://doi.org/10.4103%2F0973-029X.174632 Immunofluorescence in oral lesions https://doi.org/10.4103/jomfp.jomfp_207_17 Oral mucosal ulceration - a clinician's guide to diagnosis and treatment