**THE UNIVERSITY OF WESTERN AUSTRALIA** **Allergies and immune mediated disease II** **Dr Agnieszka Frydrych**  #### Course Presentation Overview This session continues the examination of immunological conditions, specifically focusing on allergies and immune-mediated diseases as presented by Dr. Agnieszka Frydrych at The University of Western Australia. A close-up photo of oral mucosa showing redness and white patches, likely indicating a condition related to allergies or immune-mediated disease. The image is part of a presentation slide from The University of Western Australia. # **Why is this important?** * **Many are common problems** * **Others important as may be life threatening** <img src="speaker_icon.png" alt="Speaker icon indicating audio playback potential"> #### Why is this important? - Many are common problems - Others are important as they may be life-threatening **Transient lingual papillitis** * **Aetiology and pathogenesis** * $\checkmark$ Unknown * ? Local irritation * ? Stress * ? GI disease * ? Hormonal * ? Infection * ? Hypersensitivity  The cause of this condition is currently unknown, though several potential factors have been suggested: - Local irritation - Stress - Gastrointestinal (GI) disease - Hormonal factors - Infection - Hypersensitivity A small speaker icon with sound waves emanating from it, located in the bottom right corner of the slide, likely indicating an audio component or annotation. **Transient lingual papillitis** * **Clinical features**  *(Content intentionally left blank based on source page)* A close-up clinical photograph of a tongue showing transient lingual papillitis, characterized by small, white or yellowish papules on the tongue's surface, illustrating the condition's clinical features. **Transient lingual papillitis** **Transient lingual papillitis** * **Histopathology** * $\checkmark$ Hyperkeratosis or **ulceration** * $\checkmark$ Small vascular channels in underlying lamina propria * $\checkmark$ Inflammatory cell infiltrate  - Hyperkeratosis or ulceration - Small vascular channels in the underlying lamina propria - Inflammatory cell infiltrate A histopathological image showing tissue from transient lingual papillitis, displaying hyperkeratosis or ulceration, small vascular channels in the underlying lamina propria, and an inflammatory cell infiltrate, consistent with the listed findings. <font color="yellow">**Transient lingual papillitis**</font> * **Treatment** * <font color="green">resolves without therapy</font> <img src="icon.png" alt="Speaker icon">  - The condition typically resolves without therapy. A speaker icon with sound waves emanating from it, located in the bottom right corner of the slide. The icon is a graphical representation of audio or sound, likely indicating an audio component related to the presentation content. **Recurrent aphthous stomatitis** $\blacksquare$ **Aetiology and pathogenesis** $\checkmark$ Idiopathic $\checkmark$ Local cell mediated immune response involving CD8+ T-cells, NK cells, macrophages and mast cells. $\checkmark$ Genetic predisposition  - Idiopathic - Local cell-mediated immune response involving: - CD8+ T-cells - NK cells - Macrophages - Mast cells - Genetic predisposition A close-up photo of the oral cavity showing recurrent aphthous stomatitis, with visible white ulcers on the gingiva and mucosa, illustrating the clinical presentation of the condition discussed in the text. **Recurrent aphthous stomatitis** - **Clinical features** - $\checkmark$ Minor - $\checkmark$ Major - $\checkmark$ Herpetiform $\left(\text{speaker icon}\right)$    The condition presents in three clinical forms: - Minor - Major - Herpetiform Close-up photo of a mouth showing a large, red, inflamed area on the inner lip, likely representing a major aphthous ulcer, associated with the clinical features of recurrent aphthous stomatitis. Photo showing multiple small, clustered ulcers on the floor of the mouth, characteristic of herpetiform aphthous stomatitis, with the tongue and teeth visible. Photo of a single, large, round ulcer on the inner cheek, illustrating a minor aphthous ulcer, with surrounding healthy mucosa and teeth in view. **Recurrent aphthous stomatitis** * **Histopathology** <img src="image.png" alt="Histopathology slide showing inflammation under the epithelium">  *(Visual evidence of inflammation under the epithelium provided in source)* Histopathology slide showing inflammation under the epithelium, with a dense infiltrate of inflammatory cells in the lamina propria, characteristic of recurrent aphthous stomatitis. # **Recurrent aphthous stomatitis** * **Differential diagnosis** * $\checkmark$ **Behcete’s syndrome** * $\checkmark$ **Celiac disease** * $\checkmark$ **Cyclic neutropenia** * $\checkmark$ **Nutritional deficiencies** * $\checkmark$ **Immunodeficiency** * $\checkmark$ **Inflammatory bowel disease** * $\checkmark$ **Other**  - Behcet’s syndrome - Celiac disease - Cyclic neutropenia - Nutritional deficiencies - Immunodeficiency - Inflammatory bowel disease - Other related systemic conditions A bulleted list under the heading 'Differential diagnosis' for recurrent aphthous stomatitis, including conditions such as Behcete's syndrome, Celiac disease, Cyclic neutropenia, Nutritional deficiencies, Immunodeficiency, Inflammatory bowel disease, and Other, each marked with a green checkmark. # **Recurrent aphthous stomatitis** * **Treatment** * $\checkmark$ Remove predisposing factors * $\checkmark$ Good OH * $\checkmark$ Medication * $\checkmark$ Corticosteroids * $\checkmark$ Tetracycline * $\checkmark$ Systemic immuno-modulators  - Remove predisposing factors - Maintain good oral hygiene (OH) - Medication: - Corticosteroids - Tetracycline - Systemic immuno-modulators A speaker icon with sound waves, likely indicating an audio component or a note about audio narration for the presentation slide. **Orofacial granulomatosis** **Orofacial granulomatosis** * **Aetiology and pathogenesis** * **Unknown** * **A delayed type of hypersensitivity reaction** - Unknown - Considered a delayed type of hypersensitivity reaction # Orofacial granulomatosis ## Clinical features     *(Content continues on following page)* Close-up photograph of a patient's oral cavity showing inflamed and swollen gingival tissue, characteristic of orofacial granulomatosis. The image highlights the redness and hypertrophy of the gums, with visible teeth and a dental retractor in place. Photograph of the oral cavity displaying prominent swelling and erythema of the buccal mucosa, indicative of orofacial granulomatosis. The image captures the thickened tissue and altered texture of the cheek lining. Image showing significant enlargement and redness of the labial and buccal mucosa, with a visible dental retractor. This clinical photograph illustrates the typical presentation of orofacial granulomatosis affecting the lips and cheeks. Close-up view of the oral mucosa revealing multiple small nodules and a cobblestone appearance, consistent with orofacial granulomatosis. The image highlights the texture and surface changes of the affected tissue. **Orofacial granulomatosis** - **Clinical features**  *(Clinical features section placeholder)* A close-up photo showing a patient's lower face with prominent lip swelling, consistent with orofacial granulomatosis. The lips are enlarged and have a smooth, glossy appearance, with some fine lines visible on the surface. The surrounding skin appears slightly discolored with small pigmented spots, and the overall presentation illustrates the clinical features of the condition. **Orofacial granulomatosis** ▪ **Histopathology** <img src="image1.png" alt="Histopathology images of Orofacial granulomatosis">   *(Histopathology images provided in source)* Histopathology image showing tissue sections with granulomatous inflammation, characterized by dense cellular infiltrates and epithelioid histiocytes, consistent with orofacial granulomatosis. Histopathology image displaying granulomatous lesions with central necrosis and surrounding inflammatory cells, illustrating the characteristic features of orofacial granulomatosis. **Orofacial granulomatosis** * **Differential diagnosis** * $\checkmark$ Idiopathic OFG * $\checkmark$ Crohn's Disease * $\checkmark$ Sarcoidosis * $\checkmark$ Infections * $\checkmark$ Food or Contact Allergies * $\checkmark$ Other  - Idiopathic OFG - Crohn's Disease - Sarcoidosis - Infections - Food or Contact Allergies - Other granulomatous diseases A bulleted list under the heading "Differential diagnosis" for orofacial granulomatosis, listing conditions such as Idiopathic OFG, Crohn's Disease, Sarcoidosis, Infections, Food or Contact Allergies, and Other, each marked with a green checkmark. **<font color="yellow">Orofacial granulomatosis</font>** * **Treatment** * <font color="lime">Address cause</font> * <font color="lime">Corticosteroids</font> * <font color="lime">Other</font>  - Address underlying cause - Corticosteroids - Other therapies as indicated A small speaker icon with sound waves emanating from it, located in the bottom right corner of the slide. The icon is gray with a white outline and represents audio or sound functionality. **Wegener’s granulomatosis** - **Aetiology and pathogenesis** - $\checkmark$ Unknown - $\checkmark$ Abnormal immune reaction  - Unknown - Abnormal immune reaction A speaker icon with sound waves, likely indicating audio playback, located in the bottom right corner of the slide. **Wegener’s granulomatosis** - **Clinical features**   *(Clinical features section placeholder)* Close-up photograph of the oral cavity showing inflamed and reddened gums, with visible teeth and a dental instrument, illustrating clinical features of Wegener's granulomatosis. Another close-up photograph of the mouth, highlighting inflamed gums and teeth, consistent with the clinical presentation of Wegener's granulomatosis. **Wegener's granulomatosis** * **Histopathology**  *(Histopathology section placeholder)* A histopathological image of Wegener's granulomatosis, showing a dense infiltrate of inflammatory cells with necrotic tissue, characteristic of the disease. The image displays a mix of pink and purple staining, indicating cellular and extracellular matrix components under microscopic view. **Wegener's granulomatosis** ■ **Diagnosis** $\checkmark$ **Histopathology** $\checkmark$ **ANCA ($\textit{anti-neutrophil cytoplasm antibodies}$)** - Histopathology - ANCA (anti-neutrophil cytoplasm antibodies) # **Wegener’s granulomatosis** * **Treatment** * $\checkmark$ Oral prednisolone * $\checkmark$ Cyclophosphamide - Oral prednisolone - Cyclophosphamide **Perioral dermatitis** * **Aetiology and pathogenesis** * $\checkmark$ **Idiosyncratic response to a variety of exogenous substances** * $\rightarrow$ **Tartar control toothpaste** * $\rightarrow$ **Bubble gum** * $\rightarrow$ **Cosmetic products** * $\Rightarrow$ **Some produce irritant / allergic contact dermatitis; others induce proliferation of skin flora**  - Idiosyncratic response to a variety of exogenous substances: - Tartar control toothpaste - Bubble gum - Cosmetic products - These may produce irritant/allergic contact dermatitis or induce proliferation of skin flora. A hierarchical diagram under the heading 'Aetiology and pathogenesis' detailing an idiosyncratic response to exogenous substances. It lists tartar control toothpaste, bubble gum, and cosmetic products as triggers, with a note that some cosmetic products cause irritant/allergic contact dermatitis while others induce proliferation of skin flora. **Perioral dermatitis** * **Clinical features**   *(Clinical features section placeholder)* Close-up photograph showing perioral dermatitis with red, inflamed papules and pustules around the mouth area, illustrating the clinical features of the condition. Another photograph displaying perioral dermatitis with diffuse erythema and small papules surrounding the lips, highlighting the characteristic rash pattern. **Perioral dermatitis** **Perioral dermatitis** * **Histopathology** * $\checkmark$ Chronic lymphohistiocytic dermatitis * $\checkmark$ Peri-follicular granulomatous inflammation - Chronic lymphohistiocytic dermatitis - Peri-follicular granulomatous inflammation **Perioral dermatitis** - **Treatment** - $\checkmark$ Oral tetracycline or erythromycin - $\checkmark$ Topical metronidazole or erythromycin <img src="speaker_icon.png" alt="Speaker icon">  - Oral tetracycline or erythromycin - Topical metronidazole or erythromycin A speaker icon with sound waves, likely indicating an audio feature or alert, positioned at the bottom right of the slide. <span style="color:yellow;">**Allergic contact stomatitis**</span> - **Aetiology and pathogenesis** - $\checkmark$ **Hypersensitivity to allergens is commonly observed in the oral cavity** - $\checkmark$ **Numerous substances may be involved** Allergic contact stomatitis - Hypersensitivity to allergens is commonly observed in the oral cavity. - Numerous substances may be involved. **Allergic contact stomatitis** * **Clinical features** * $\checkmark$ Erythema * $\checkmark$ Oedema <img src='Allergic contact stomatitis clinical features images'>   - Erythema - Oedema Close-up photograph showing erythema and oedema in the oral cavity, with a visible dental prosthesis, illustrating clinical features of allergic contact stomatitis. Photograph of the oral cavity displaying widespread erythema and oedema, consistent with the clinical features of allergic contact stomatitis. **Allergic contact stomatitis** - **Histopathology** - $\checkmark$ Spongiosis - $\checkmark$ Engorged and dilated blood vessels - $\checkmark$ Lymphocytes - $\checkmark$ Plasma cells Contact stomatitis from cinnamon  Findings often seen in cases such as contact stomatitis from cinnamon: - Spongiosis - Engorged and dilated blood vessels - Lymphocytes - Plasma cells Microscopic image of tissue showing histopathological features of allergic contact stomatitis, with spongiosis, engorged and dilated blood vessels, lymphocytes, and plasma cells. The image is labeled 'Contact stomatitis from cinnamon' and displays a pink and purple stained tissue section under magnification. **Allergic contact stomatitis** - **Treatment** - $\checkmark$ Eliminate allergen - $\checkmark$ Antihistamine - $\checkmark$ Topical corticosteroid <br> <br> <br>  - Eliminate allergen - Antihistamine - Topical corticosteroid A bulleted list under the heading 'Treatment' for allergic contact stomatitis, featuring three checked items: 'Eliminate allergen', 'Antihistamine', and 'Topical corticosteroid'. The text is displayed in white on a blue background with green checkmarks. # **Angioedema** * **Aetiology and pathogenesis** * **Allergic** * **Drug-induced (non-allergic)** * **Hereditary (C1 esterase inhibitor deficiency)**  - Allergic - Drug-induced (non-allergic) - Hereditary (C1 esterase inhibitor deficiency) A detailed diagram illustrating the complement system pathways, including the classical and alternative pathways, with labeled components such as C1, C4, C3, C5, and various factors like C1-INH, MASP, and Factor H. The diagram shows interactions and cascades leading to the formation of the membrane attack complex (MAC) and other downstream effects. **Angioedema** * **Clinical features**  *(Clinical features section placeholder)* A close-up photograph showing severe angioedema of the lips, with significant swelling and a glossy, red appearance. The image is presented under the heading 'Angioedema' and the subheading 'Clinical features', illustrating a typical clinical presentation of the condition. # **Angioedema** * **Diagnosis** * **History** * **Serum C3, C4 levels and C1 esterase inhibitor activity** - History - Serum C3, C4 levels and C1 esterase inhibitor activity **Angioedema** - **Treatment** - $\checkmark$ **Severe cases: medical emergency – adrenaline** - $\checkmark$ **Corticosteroids** - $\checkmark$ **Antihistamines** - $\blacksquare$ **Prevention important** - Severe cases: medical emergency – adrenaline - Corticosteroids - Antihistamines - Prevention is important # **Erythema migrans** * Also referred to as: **geographic tongue** and **benign migratory glossitis** * Aetiology and pathogenesis * $\checkmark$ Common genetic condition of unknown cause * $\checkmark$ May be associated with other conditions Also referred to as geographic tongue and benign migratory glossitis. - Common genetic condition of unknown cause - May be associated with other conditions # **Erythema migrans** * **Clinical features** * $\checkmark$ Common (2% of US population) * $\checkmark$ F>M * $\checkmark$ More common in young, non-smokers and atopic individuals * $\checkmark$ Usually affects dorsal surface of the tongue * $\checkmark$ Usually asymptomatic * $\checkmark$ May be associated with fissured tongue - Common (2% of US population) - Females > Males - More common in young, non-smokers, and atopic individuals - Usually affects the dorsal surface of the tongue - Usually asymptomatic - May be associated with fissured tongue **Erythema migrans**    *(Page contains title only)* Close-up photo of a tongue showing erythema migrans, characterized by a red, inflamed surface with white, patchy areas resembling a migratory rash. Photo of oral mucosa displaying erythema migrans with a red, inflamed lesion and a distinct white border, indicating a migratory pattern of the rash. Photo of the oral cavity showing erythema migrans with a red, inflamed area on the palate and surrounding tissue, with white, irregular borders and visible teeth. # **Erythema migrans** * **Histopathology** <img src="image_of_tongue_lesion.png" alt="Image of a tongue with a migratory, map-like lesion"> <img src="image_of_histopathology_slide.png" alt="Image of a histopathology slide showing inflammation beneath the epithelium">   *(Histopathology images showing migratory map-like lesions and inflammation beneath the epithelium provided in source)* A histopathology slide showing a tissue sample with inflammation beneath the epithelium, characterized by a dense infiltration of cells in the subepithelial region. A clinical photo of a tongue with a migratory, map-like lesion, consistent with erythema migrans, showing a red, irregularly shaped lesion with a white border. Erythema migrans * Differential diagnosis * Candidiosis * Leukoplakia * Oral lichen planus * Lupus erythematosus  - Candidiosis - Leukoplakia - Oral lichen planus - Lupus erythematosus A small speaker icon with sound waves, indicating audio or sound functionality, located in the bottom right corner of the slide. # **Erythema migrans** - **Treatment** - $\checkmark$ Usually none required - $\checkmark$ Topical corticosteroids for symptomatic cases  - Usually none required - Topical corticosteroids for symptomatic cases A gray speaker icon with sound waves emanating from it, located in the bottom right corner of the slide, likely indicating an audio feature or narration. # **Pemphigus** * **Aetiology and pathogenesis** * $\checkmark$ Group of chronic autoimmune diseases characterised by epithelial blistering affecting mucocutaneous surfaces * $\checkmark$ Autoantibodies directed against desmosomes - Group of chronic autoimmune diseases characterised by epithelial blistering affecting mucocutaneous surfaces - Autoantibodies directed against desmosomes **Pemphigus** <img src="image1.png" alt="Micrograph showing intercellular space enlargement (acantholysis) characteristic of pemphigus, next to a diagram illustrating desmosomal components like Desmoglein 1, Desmoglein 3, Desmocollin, and their association with Desmoplakin and Plakoglobin within an epithelial cell structure."> <table> <tr> <td> Desmoglein 1 </td> <td> $\longrightarrow$ </td> <td> [Diagrammatic representation of desmosomal connection] </td> <td> Desmoplakin </td> </tr> <tr> <td> Desmoglein 3 </td> <td> $\longrightarrow$ </td> <td> [Diagrammatic representation of desmosomal connection] </td> <td> [Part of cell structure] </td> </tr> <tr> <td> Desmocollin </td> <td> $\longrightarrow$ </td> <td> [Diagrammatic representation of desmosomal connection] </td> <td> Plakoglobin </td> </tr> </table>   #### Desmosomal Components and Autoantibodies - Desmoglein 1 - Desmoglein 3 - Desmocollin - Desmoplakin - Plakoglobin *(Micrograph shows intercellular space enlargement/acantholysis)* Micrograph showing intercellular space enlargement (acantholysis) characteristic of pemphigus, with visible separation of epithelial cells stained in purple and pink. Diagram illustrating the components of desmosomes in epithelial cells, showing Desmoglein 1, Desmoglein 3, and Desmocollin connecting to Desmoplakin and Plakoglobin within the cell structure. **Pemphigus** | Pemphigus variants | Autoantibody implicated | | | :--- | :--- | :--- | | Foliaceous $\longrightarrow$ | Desmoglein 1 | **[1] Autoantibodies against desmoglein** $\downarrow$ | | Vulgaris (Vegetans is a variant) $\longrightarrow$ | Desmoglein 3 | **[2] Acantholysis** | | IgA pemphigus $\longrightarrow$ | Desmoglein 2 | | | Paraneoplastic pemphigus $\longrightarrow$ | Desmoplakin | **[3] Acantholytic cells** |   #### Pemphigus Variants and Implicated Autoantibodies 1. **Foliaceous**: Desmoglein 1 2. **Vulgaris (Vegetans is a variant)**: Desmoglein 3 3. **IgA pemphigus**: Desmoglein 2 4. **Paraneoplastic pemphigus**: Desmoplakin #### Pathological Process - Autoantibodies against desmoglein - Acantholysis - Acantholytic cells A diagram illustrating pemphigus variants and their associated autoantibodies, showing a vertical arrangement of skin cells with labels for Foliaceous (Desmoglein 1), Vulgaris (Desmoglein 3), IgA pemphigus (Desmoglein 2), and Paraneoplastic pemphigus (Desmoplakin). A three-step diagram explaining the pathogenesis of pemphigus: 1) Autoantibodies against desmoglein lead to cell separation, 2) Acantholysis showing detached keratinocytes, and 3) Acantholytic cells as the result of cell loss. **Pemphigus vulgaris** **Clinical features** $\checkmark$ Most severe form $\checkmark$ Middle aged and older individuals $\checkmark$ F>M $\checkmark$ Individuals of Ashkenazi, Asian or Mediterranean descent $\checkmark$ Genetic and other predisposing factors $\checkmark$ Oral and skin lesions - Most severe form - Middle-aged and older individuals - Females > Males - Individuals of Ashkenazi, Asian, or Mediterranean descent - Genetic and other predisposing factors - Oral and skin lesions **Pemphigus vulgaris** * **Clinical features**   *(Clinical features section placeholder)* A close-up photo showing oral lesions in a patient with pemphigus vulgaris, characterized by erosions and ulcerations on the mucosal surfaces of the mouth, including the tongue and palate. A photo depicting skin lesions on the legs of a patient with pemphigus vulgaris, showing multiple erythematous plaques, blisters, and crusted areas, illustrating the cutaneous manifestations of the disease. **Pemphigus vulgaris**   *(Page contains title only)* A close-up photo showing extensive skin lesions on a patient's torso, consistent with pemphigus vulgaris, featuring large, painful erosions and crusted areas. A photo of a patient lying in bed with widespread erythematous and crusted lesions across the face, neck, and upper body, illustrating severe pemphigus vulgaris. **Pemphigus vulgaris** * **Histopathology** <img src="image_description.png" alt="Two images showing histopathology findings for Pemphigus vulgaris. The left image is a micrograph (likely H&E stain) showing an Intraepithelial Cleft and Acantholitic Cells, with the Basal Cell Layer indicated. The right image shows fluorescence microscopy indicating Intercellular Deposition of IgG in a chicken-wire pattern.">  - Intraepithelial Cleft - Acantholytic Cells - Basal Cell Layer involvement - Intercellular Deposition of IgG in a "chicken-wire" pattern (Direct Immunofluorescence) A composite image showing two histopathological findings for Pemphigus vulgaris. The left panel is a micrograph of an H&E stain demonstrating an intraepithelial cleft, acantholytic cells, and the basal cell layer. The right panel is a fluorescence microscopy image showing intercellular deposition of IgG in a characteristic chicken-wire pattern. **Pemphigus vulgaris** - **Histopathology**  *(Histopathology section placeholder)* A histopathological image showing pemphigus vulgaris, characterized by acantholysis with intraepidermal blister formation and scattered keratinocytes. The image displays a section of skin tissue with prominent separation of epithelial cells, resulting in a 'dumbbell' or 'tombstone' appearance of the remaining cells. # **Pemphigus vulgaris** * **Differential diagnosis** * $\checkmark$ **Paraneoplastic pemphigus** * $\checkmark$ **Mucous membrane pemphigoid** * $\checkmark$ **Erythema multiforme** * $\checkmark$ **Oral lichen planus** - Paraneoplastic pemphigus - Mucous membrane pemphigoid - Erythema multiforme - Oral lichen planus **Pemphigus vulgaris** **Treatment** * **Treatment** * $\checkmark$ Corticosteroids * $\checkmark$ Steroid sparing immuno-suppressants (azathioprine, dapsone, mycophenolate, cyclophosphamide) * $\checkmark$ Rituximab - Corticosteroids - Steroid-sparing immuno-suppressants: - Azathioprine - Dapsone - Mycophenolate - Cyclophosphamide - Rituximab **Pemphigoid** **Aetiology and pathogenesis** $\checkmark$ Group of sub-epithelial immunologically mediated vesiculobullous disorders that affect stratified squamous epithelium and are characterised by damage to one of the protein constituents of the BMZ anchoring filament components - Group of sub-epithelial immunologically mediated vesiculobullous disorders - Affects stratified squamous epithelium - Characterised by damage to protein constituents of the Basement Membrane Zone (BMZ) anchoring filament components **Pemphigoid**  *(Page contains title only)* A diagram illustrating the structure of the basement membrane in pemphigoid, showing various components such as BP 1, BP 2, laminin, epiligrin, collagen IV, and collagen VII, with arrows indicating their positions and interactions within the skin layers. **Mucous Membrane Pemphigoid** 1 Antibody 2 Antibody binds to antigen(s) 3 Complement activated 4 Leukocyte infiltration and BMZ damage  #### Pathogenesis Sequence 1. Antibody production 2. Antibody binds to antigen(s) 3. Complement activated 4. Leukocyte infiltration and BMZ damage A diagram illustrating the pathogenesis of Mucous Membrane Pemphigoid, showing four steps: 1) Antibody formation, 2) Antibody binding to antigens on cell surfaces, 3) Complement activation, and 4) Leukocyte infiltration leading to basement membrane zone (BMZ) damage. The diagram depicts cells with antibodies attaching to surface antigens, resulting in immune-mediated tissue injury. **Mucous Membrane Pemphigoid** * **Clinical features** * $\checkmark$ **F>M** * $\checkmark$ **$5^{th}-6^{th}$ decade** * $\checkmark$ **No known geographic incidence** * $\checkmark$ **Genetic predisposition** * $\checkmark$ **May be drug induced** * $\checkmark$ **Extra-oral involvement: ocular, laryngeal, nasal, genital, skin**  - Females > Males - 5th–6th decade - No known geographic incidence - Genetic predisposition - May be drug-induced - Extra-oral involvement: ocular, laryngeal, nasal, genital, skin A bulleted list under the heading "Clinical features" detailing characteristics of Mucous Membrane Pemphigoid, including female predominance (F>M), onset in the 5th-6th decade, no known geographic incidence, genetic predisposition, potential drug induction, and extra-oral involvement in ocular, laryngeal, nasal, genital, and skin areas. **Mucous Membrane Pemphigoid** * **Clinical features**   *(Clinical features section placeholder)* A close-up photograph showing a blister on the mucous membrane, likely representing a clinical feature of mucous membrane pemphigoid. The image highlights a fluid-filled lesion on the oral mucosa. A photograph depicting extensive mucosal involvement with erosions and ulcerations in the oral cavity, consistent with the clinical presentation of mucous membrane pemphigoid. The image shows exposed tissue and dental structures. **Mucous Membrane Pemphigoid** * **Clinical features** <img src="image_of_eye_and_skin_lesions_related_to_mucous_membrane_pemphigoid.jpg" alt="Image showing clinical features of Mucous Membrane Pemphigoid, including involvement of the eye (conjunctival inflammation/lesion) and skin erosions/ulcerations.">   #### Extra-oral Manifestations - Ocular involvement (conjunctival inflammation/lesions) - Skin erosions and ulcerations A photograph showing skin lesions on the arm, characterized by red, inflamed, and ulcerated areas, illustrating the clinical features of Mucous Membrane Pemphigoid. A close-up photograph of an eye with severe conjunctival inflammation and erosion, demonstrating the ocular involvement in Mucous Membrane Pemphigoid. **Mucous Membrane Pemphigoid** * **Histopathology** <img src="image_description.png" alt="Two images showing microscopic views related to Mucous Membrane Pemphigoid. The left image is stained with H&E showing epithelial tissue separation from the underlying connective tissue with inflammatory infiltrate. The right image shows a linear pattern of immune deposits along the basement membrane zone under direct immunofluorescence.">   - H&E: Epithelial tissue separation from the underlying connective tissue with inflammatory infiltrate - Direct Immunofluorescence: Linear pattern of immune deposits along the basement membrane zone Microscopic view of mucous membrane pemphigoid histopathology showing epithelial separation from the underlying connective tissue with inflammatory infiltrate, stained with H&E. Direct immunofluorescence image displaying a linear pattern of immune deposits along the basement membrane zone, characteristic of mucous membrane pemphigoid. # Mucous Membrane Pemphigoid * Differential diagnosis * Oral lichen planus * Pemphigus * Angina bullosa haemorrhagica * Dermatitis herpetiformis * Linear IgA disease * Erythema multiforme  - Oral lichen planus - Pemphigus - Angina bullosa haemorrhagica - Dermatitis herpetiformis - Linear IgA disease - Erythema multiforme A small speaker icon with sound waves, indicating audio or sound functionality, located in the bottom right corner of the slide. **Mucous Membrane Pemphigoid** * **Treatment** * $\checkmark$ Corticosteroids * $\checkmark$ Steroid sparing immuno-suppressants * $\checkmark$ Rituximab  - Corticosteroids - Steroid-sparing immuno-suppressants - Rituximab A bulleted list under the heading 'Treatment' for Mucous Membrane Pemphigoid, showing three treatment options: Corticosteroids, Steroid sparing immuno-suppressants, and Rituximab, each marked with a green checkmark. # **Linear IgA disease** ■ **Aetiology and pathogenesis** $\checkmark$ **Chronic autoimmune disease of the skin that commonly affects the mucous membranes including the gingiva** $\checkmark$ **Autoantibodies to BP180 (collagen XVII)** - Chronic autoimmune disease of the skin that commonly affects the mucous membranes, including the gingiva - Autoantibodies to BP180 (collagen XVII) **Linear IgA disease** **Clinical features** $\checkmark$ Skin lesions may be urticarial, annular, targetoid or bullous $\checkmark$ Oral lesions are ulcerative (preceded by bullae) or erosive   - Skin lesions: May be urticarial, annular, targetoid, or bullous - Oral lesions: Ulcerative (preceded by bullae) or erosive A photograph showing skin lesions with urticarial, annular, and bullous characteristics, illustrating the clinical features of Linear IgA disease as described in the text. A photograph of oral lesions in Linear IgA disease, displaying ulcerative and erosive areas on the mucosa, with arrows pointing to specific affected regions. # **Linear IgA disease** * **Histopathology**   *(Histopathology section placeholder)* Histopathological image showing a tissue section with pink and purple staining, indicating cellular structures and inflammation, likely from a skin biopsy in Linear IgA disease. Fluorescence microscopy image displaying a green-stained linear pattern along the basement membrane, characteristic of immunofluorescence findings in Linear IgA disease. **Linear IgA disease** **Linear IgA disease** * **Differential diagnosis** * $\checkmark$ Oral lichen planus * $\checkmark$ Mucous membrane pemphigoid * $\checkmark$ Pemphigus vulgaris * $\checkmark$ Chronic ulcerative stomatitis  - Oral lichen planus - Mucous membrane pemphigoid - Pemphigus vulgaris - Chronic ulcerative stomatitis A bulleted list under the heading "Differential diagnosis" for Linear IgA disease, listing four conditions: Oral lichen planus, Mucous membrane pemphigoid, Pemphigus vulgaris, and Chronic ulcerative stomatitis, each marked with a green checkmark. **Linear IgA disease** **Linear IgA disease** * **Treatment** $\checkmark$ Topical / systemic corticosteroids $\checkmark$ **Other immunosuppressive agents may be** **used in more severe or refractory cases** - Topical / systemic corticosteroids - Other immunosuppressive agents may be used in more severe or refractory cases <p style="text-align: center;"><span style="color: #ffff00; font-size: 36px;"><b>Erythema multiforme</b></span></p> <ul> <li><span style="color: #ffffff; font-size: 28px;"><b>Aetiology and </b></span></li> <li><span style="color: #ffffff; font-size: 28px;"><b>pathogenesis</b></span> <ul> <li><span style="color: #00ff00;"><b>✓ Acute, often recurrent, non-</b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>immediate allergic </b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>hypersensitivity reaction </b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>affecting mucocutaneous </b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>tissues, characterised by </b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>serosanguinous exudates on </b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>the lips, mucosal ulceration or </b></span></li> <li><span style="color: #ffffff; font-size: 24px;"><b>target like lesions on the skin</b></span></li> </ul> </li> </ul> <p style="text-align: left;"><span style="color: #ffffff; font-size: 20px;"><b>Note: </b></span><span style="color: #ff9900; font-size: 20px;"><b>Steven-Johnson</b></span></p> <p style="text-align: left;"><span style="color: #ff9900; font-size: 20px;"><b>syndrome / toxic</b></span></p> <p style="text-align: left;"><span style="color: #ff9900; font-size: 20px;"><b>epidermal necrolysis</b></span></p> <img src="image.png" alt="Close-up of a person's mouth showing severe mucosal ulceration and serosanguinous exudate on the lips, consistent with erythema multiforme or related conditions. A speaker icon is visible in the lower right corner.">  - Acute, often recurrent, non-immediate allergic hypersensitivity reaction affecting mucocutaneous tissues - Characterised by: - Serosanguinous exudates on the lips - Mucosal ulceration - Target-like lesions on the skin **Note:** Stevens-Johnson syndrome / toxic epidermal necrolysis are related conditions. Close-up photograph of a person's mouth showing severe mucosal ulceration and serosanguinous exudate on the lips, consistent with erythema multiforme. The image is positioned next to text describing the condition's aetiology and pathogenesis, including characteristics like mucosal ulceration and target-like lesions. # **Erythema multiforme** * **Aetiology and pathogenesis** * $\checkmark$ Infections * $\checkmark$ Drugs * $\checkmark$ Vaccines * $\checkmark$ Food additives / chemicals * $\checkmark$ Radiation therapy #### Potential Triggers - Infections - Drugs - Vaccines - Food additives / chemicals - Radiation therapy **Erythema multiforme** * **Aetiology and pathogenesis** * $\checkmark$ Presentation of antigens to T lymphocytes initiates the immune reaction * $\checkmark$ Effector cells: CD8+ T-cells, Macrophages and PMNL #### Immunological Mechanism - Presentation of antigens to T lymphocytes initiates the immune reaction - Effector cells: CD8+ T-cells, Macrophages, and PMNL **Erythema multiforme** **Clinical features** * **Peak incidence 20-40y** * **M>F** * **Worldwide** * **Genetic predisposition** - Peak incidence: 20–40 years - Males > Females - Worldwide occurrence - Genetic predisposition    *(Content intentionally left blank based on source page)* Close-up photo of a patient's mouth showing severe erythema and ulcerations on the lips and oral mucosa, consistent with a multifocal erythema condition. Photo of the oral cavity displaying extensive erythema and white patches on the tongue and surrounding mucosa, indicative of a multifocal inflammatory or infectious process. Photo of a hand with multiple erythematous, raised lesions on the palm and fingers, illustrating a systemic manifestation of multifocal erythema. **Erythema multiforme** * **Histopathology**  *(Histopathology section placeholder)* A histopathological image showing skin tissue with epidermal changes, including vacuolar degeneration of basal keratinocytes and a dense inflammatory infiltrate in the dermis, consistent with erythema multiforme. The image is presented under the heading 'Histopathology' and illustrates characteristic features of the condition. **Erythema multiforme** * **Differential diagnosis** * $\checkmark$ HSV * $\checkmark$ Aphthous ulcers * $\checkmark$ Pemphigus vulgaris * $\checkmark$ Mucous membrane pemphigoid * $\checkmark$ Oral lichen planus - Herpes Simplex Virus (HSV) - Aphthous ulcers - Pemphigus vulgaris - Mucous membrane pemphigoid - Oral lichen planus <font color='yellow'>Erythema multiforme</font> **Erythema multiforme** * **Treatment** * $\checkmark$ Corticosteroids * $\checkmark$ May require hospitalization * $\checkmark$ Avoid triggers! <img src="speaker_icon.png" alt="Speaker icon">  - Corticosteroids - May require hospitalization - Avoid triggers A speaker icon located in the bottom right corner of the slide, indicating audio content. The icon is a simple graphic with sound waves emanating from it, set against a blue background. **Chronic ulcerative stomatitis** * **Aetiology and pathogenesis** * $\checkmark$ **Rare immune-mediated mucocutaneous disorder that produces desquamation and ulceration of oral mucosa**  - Rare immune-mediated mucocutaneous disorder that produces desquamation and ulceration of oral mucosa A small icon of a speaker with sound waves, located in the bottom right corner of the slide, likely indicating an audio component. **Chronic ulcerative stomatitis** * **Clinical features** * $\checkmark$ Resembles other mucocutaneous conditions * $\checkmark$ Usually affects older white women * $\checkmark$ Tongue, buccal mucosa and gingiva usually affected - Resembles other mucocutaneous conditions - Usually affects older white women - Tongue, buccal mucosa, and gingiva are usually affected **Chronic ulcerative stomatitis** **Clinical features**   *(Clinical features section placeholder)* Close-up photo showing chronic ulcerative stomatitis with multiple red, inflamed ulcers on the gingival tissue and surrounding oral mucosa, adjacent to teeth. Close-up photo of chronic ulcerative stomatitis displaying a large, erythematous, and ulcerated lesion on the buccal mucosa, with visible tissue damage and possible fibrin exudate. <p style="text-align: left; color: #FFFF00; font-weight: bold; font-size: 48px;">Chronic ulcerative stomatitis</p> <p style="text-align: left; color: #FF0000; font-weight: bold;">Chronic ulcerative stomatitis</p> <ul> <li><span style="color: #FFFFFF;">Histopathology</span> <ul> <li><span style="color: #00FF00;">H&E: resembles OLP</span></li> <li><span style="color: #00FF00;">DI: perinuclear</span></li> <li><span style="color: #FFFFFF;">deposits of IgG in</span></li> <li><span style="color: #FFFFFF;">basal layer and lower</span></li> <li><span style="color: #FFFFFF;">1/3 epithelial layers</span></li> </ul> </li> </ul> <img src="image_placeholder.png" alt="Microscopic image showing green fluorescence in epithelial layers">  - **H&E**: Resembles Oral Lichen Planus (OLP) - **Direct Immunofluorescence (DI)**: Perinuclear deposits of IgG in the basal layer and lower 1/3 of epithelial layers Microscopic image showing green fluorescence in epithelial layers, illustrating perinuclear deposits of IgG in the basal layer and lower 1/3 of the epithelial layers, consistent with histopathological findings of chronic ulcerative stomatitis. **Chronic ulcerative stomatitis** * **Differential diagnosis** * $\checkmark$ Oral lichen planus * $\checkmark$ Mucous membrane pemphigoid * $\checkmark$ Linear IgA disease * $\checkmark$ Pemphigus vulgaris Chronic ulcerative stomatitis Chronic ulcerative stomatitis  - Oral lichen planus - Mucous membrane pemphigoid - Linear IgA disease - Pemphigus vulgaris A small speaker icon with sound waves, likely indicating an audio feature or alert, located on the right side of the slide. Chronic ulcerative stomatitis * Treatment * Hydroxychloroquine  - Hydroxychloroquine A speaker icon with sound waves, indicating audio or sound functionality, located on a blue background. **Lupus erythematosus** **Lupus erythematosus** * **Aetiology and pathogenesis** * $\checkmark$ Autoimmune disease involving both humoral and cell mediated arms of the immune system * $\checkmark$ Antibodies directed against various cellular antigens in the nucleus and the cytoplasm - Autoimmune disease involving both humoral and cell-mediated arms of the immune system - Antibodies directed against various cellular antigens in the nucleus and the cytoplasm **Lupus erythematosus** * **Clinical features** * $\checkmark$ Occurs in three forms * $\rightarrow$ Systemic (acute) * $\rightarrow$ Discoid (chronic) * $\rightarrow$ Subacute  Occurs in three forms: - Systemic (acute) - Discoid (chronic) - Subacute A speaker icon with sound waves, likely indicating an audio feature or alert, positioned on the right side of the slide. # **Lupus erythematosus** * **Clinical features** * **DLE** * **F>M** * **Skin lesions are disk shaped erythematous plaques with hyper-pigmented margins** * **Similar to OLP**   #### Discoid Lupus Erythematosus (DLE) - Females > Males - Skin lesions are disk-shaped erythematous plaques with hyper-pigmented margins - Similar appearance to OLP A photo showing a patient's face with multiple disk-shaped erythematous plaques on the cheeks and nose, consistent with discoid lupus erythematosus (DLE). The lesions have hyper-pigmented margins, as described in the text. A close-up photo of a skin lesion on an arm, illustrating a disk-shaped erythematous plaque with hyper-pigmented margins, characteristic of DLE. This visual example supports the textual description of the clinical features. # **Lupus erythematosus**    *(Page contains title only)* Close-up photo of a patient's lips showing oral lesions, likely related to lupus erythematosus, with visible ulceration and inflammation around the mouth. Intraoral photo showing a large, erythematous ulcerative lesion on the palate, consistent with oral manifestations of lupus erythematosus. Photo of the oral cavity displaying extensive erythematous and ulcerated mucosal lesions on the gingiva and palate, indicative of lupus erythematosus. **Lupus erythematosus** * **Clinical features** * $\checkmark$ **SLE** * $\rightarrow$ Skin and mucosal lesions are mild * $\rightarrow$ Multiple organ involvement * $\rightarrow$ Serologic tests positive for autoantibodies * i. ANA * ii. Other #### Systemic Lupus Erythematosus (SLE) - Skin and mucosal lesions are mild - Multiple organ involvement - Serologic tests positive for autoantibodies: - ANA (Antinuclear Antibody) - Other specific markers **<font color="yellow">Lupus erythematosus</font>** <img src="image_description_lupus_erythematosus" alt="Images showing skin rash suggesting Lupus erythematosus and an oral ulcer."/>   *(Visual evidence of skin rash and oral ulceration provided in source)* A photo showing a person with a facial rash, characteristic of lupus erythematosus, with erythematous lesions on the cheeks and nose. A photo depicting an oral ulcer in the mouth, likely associated with lupus erythematosus, with visible mucosal involvement. <span style="color:yellow;">Lupus erythematosus</span> * <span style="color:white;">Histopathology</span> * <span style="color:lightgreen;">Basal cell</span> <span style="color:white;">destruction</span> * <span style="color:lightgreen;">Hyperkeratosis</span> * <span style="color:lightgreen;">Epithelial atrophy</span> * <span style="color:lightgreen;">Lymphocytic</span> <span style="color:white;">infiltration</span> * <span style="color:lightgreen;">Vascular dilation</span> <span style="color:white;">oedema</span>   - Basal cell destruction - Hyperkeratosis - Epithelial atrophy - Lymphocytic infiltration - Vascular dilation and oedema A histopathological image showing a tissue sample with dense lymphocytic infiltration, characteristic of lupus erythematosus. The image displays purple-stained nuclei and a disrupted epidermal layer, consistent with basal cell destruction and epithelial atrophy. A histopathological image of discoid lupus erythematosus, showing a lichenoid reaction with liquefaction degeneration and the presence of apoptotic keratinocytes. The tissue is stained pink and purple, highlighting the inflammatory infiltrate and epidermal changes. **Lupus erythematosus** * **Differential diagnosis** * $\checkmark$ Oral lichen planus * $\checkmark$ Mucous membrane pemphigoid * $\checkmark$ Pemphigus vulgaris * $\checkmark$ Erythematous candidiasis * $\checkmark$ Contact hypersensitivity <img src="image_of_speaker_icon.png" alt="Speaker icon">  - Oral lichen planus - Mucous membrane pemphigoid - Pemphigus vulgaris - Erythematous candidiasis - Contact hypersensitivity A speaker icon with sound waves, likely indicating an audio feature or playback control, located on the right side of the slide. Lupus erythematosus * Treatment * Topical / systemic corticosteroids * Other immunosuppressive agents​​​​  - Topical / systemic corticosteroids - Other immunosuppressive agents A gray speaker icon with sound waves emanating from it, indicating audio or sound functionality, located on a blue background. # **Systemic sclerosis** * **Aetiology and pathogenesis** * $\checkmark$ **Rare immunologically mediated disease** * $\checkmark$ **Dense collagen is deposited in the tissues of the body** - Rare immunologically mediated disease - Dense collagen is deposited in the tissues of the body # **Systemic sclerosis** # **Systemic sclerosis** **Clinical features** $\checkmark$ Most patients are adults $\checkmark$ F>M $\checkmark$ Raynaud’s phenomenon $\checkmark$ Diffuse, hard skin texture $\checkmark$ Multi-organ involvement  - Most patients are adults - Females > Males - Raynaud’s phenomenon - Diffuse, hard skin texture - Multi-organ involvement A photo showing two hands with a diffuse, hard skin texture, illustrating a clinical feature of systemic sclerosis. The hands are placed side by side against a dark background, highlighting the skin changes associated with the condition. <font color="yellow">**Systemic sclerosis**</font> **Systemic sclerosis** Clinical features $\checkmark$ Oral manifestations: $\rightarrow$ Microstomia $\rightarrow$ Dysphagia $\rightarrow$ Xerostomia $\rightarrow$ Widening of the PDL space <img src="speaker_icon.png" alt="Speaker icon">  #### Oral Manifestations - Microstomia - Dysphagia - Xerostomia - Widening of the PDL space A speaker icon, likely indicating an audio feature, is displayed on the right side of the slide. It is a graphical representation of a loudspeaker with sound waves emanating from it, suggesting an interactive element for audio playback related to the content on systemic sclerosis. **<font color="yellow">Systemic sclerosis</font>** <img src="image_of_patient_face_showing_skin_tightening_and_radiograph_of_jaw_and_hands_showing_sclerosis_related_signs.jpg" alt="Collage of images related to Systemic sclerosis: a close-up of a patient's face showing skin changes, a panoramic dental radiograph, and an image of hands.">    *(Visual evidence of skin tightening and radiographic signs provided in source)* A close-up photograph of a patient's face showing skin changes associated with systemic sclerosis, including tight, taut skin and a narrowed mouth. A panoramic dental radiograph showing the jaw and teeth, revealing sclerosis-related signs such as bone density changes and possible dental abnormalities. A photograph of a patient's hands, displaying skin thickening and tightening characteristic of systemic sclerosis, with a ring visible on one finger. **Systemic sclerosis** * **Histopathology** * Diffuse deposition of collagen within and around normal structures * The abnormal collagen replaces and destroys normal tissue $\rightarrow$ **loss of normal function** - Diffuse deposition of collagen within and around normal structures - Abnormal collagen replaces and destroys normal tissue, leading to loss of normal function # Systemic sclerosis * Treatment * Difficult! * Various systemic agents have been trailed with limited success - Treatment is difficult - Various systemic agents have been trialed with limited success # **CREST syndrome** * **Aetiology and pathogenesis** * $\checkmark$ Uncommon condition that is a mild variant of systemic sclerosis: * **C**alcinosis cutis * **R**aynaud’s phenomenon * **E**sophageal dysfunction * **S**clerodactyly * **T**elangiectasia  Uncommon condition that is a mild variant of systemic sclerosis, defined by the acronym: - **C**: Calcinosis cutis - **R**: Raynaud’s phenomenon - **E**: Esophageal dysfunction - **S**: Sclerodactyly - **T**: Telangiectasia A list of the CREST syndrome components, each represented by a colored letter (C, R, E, S, T) with corresponding clinical features: Calcinosi cutis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasia. The text is presented in a vertical format with a blue background. **CREST syndrome**  *(Page contains title only)* A close-up photo of a finger showing multiple white, firm nodules on the skin, characteristic of calcinosis associated with CREST syndrome. The image is framed by a blue border with the title 'CREST syndrome' in yellow text at the top. **CREST syndrome**  *(Page contains title only)* A photo showing two hands with a characteristic appearance of CREST syndrome, featuring thickened and tight skin on the fingers, particularly the index and middle fingers, against a dark background. **CREST syndrome** Sclerodactyly  #### Sclerodactyly A photograph showing hands with sclerodactyly, a symptom of CREST syndrome, characterized by thickened and tight skin on the fingers. The image is labeled 'Sclerodactyly' and illustrates the condition in the context of the syndrome. **CREST syndrome**    *(Page contains title only)* Close-up photo of a finger showing red, inflamed skin lesions, likely representing digital sclerosis or skin changes associated with CREST syndrome. Photo showing facial skin with telangiectasias and erythematous patches, characteristic of cutaneous manifestations in CREST syndrome. Photo of the oral cavity displaying mucosal telangiectasias and erythema, indicating gastrointestinal involvement common in CREST syndrome. **CREST syndrome** * **Histopathology** * $\checkmark$ Similar to systemic sclerosis * $\checkmark$ Telangiectatic vessels - Similar to systemic sclerosis - Presence of telangiectatic vessels # **CREST syndrome** * **Differential diagnosis** * $\checkmark$ **Hereditary haemorrhagic telangiectasia** * $\rightarrow$ **Anti-centromere antibodies** - Hereditary haemorrhagic telangiectasia - Diagnosis supported by anti-centromere antibodies **CREST syndrome** * **Treatment** * **As for systemic sclerosis** - Treatment protocols are the same as for systemic sclerosis [^1]: Original PDF page 1: [[L8 Allergies and immune disease II.pdf#page=1|L8 Allergies and immune disease II, p.1]] [^2]: Original PDF page 2: [[L8 Allergies and immune disease II.pdf#page=2|L8 Allergies and immune disease II, p.2]] [^3]: Original PDF page 3: [[L8 Allergies and immune disease II.pdf#page=3|L8 Allergies and immune disease II, p.3]] [^4]: Original PDF page 4: [[L8 Allergies and immune disease II.pdf#page=4|L8 Allergies and immune disease II, p.4]] [^5]: Original PDF page 5: [[L8 Allergies and immune disease II.pdf#page=5|L8 Allergies and immune disease II, p.5]] [^6]: Original PDF page 6: [[L8 Allergies and immune disease II.pdf#page=6|L8 Allergies and immune disease II, p.6]] [^7]: Original PDF page 7: [[L8 Allergies and immune disease II.pdf#page=7|L8 Allergies and immune disease II, p.7]] [^8]: Original PDF page 8: [[L8 Allergies and immune disease II.pdf#page=8|L8 Allergies and immune disease II, p.8]] [^9]: Original PDF page 9: [[L8 Allergies and immune disease II.pdf#page=9|L8 Allergies and immune disease II, p.9]] [^10]: Original PDF page 10: [[L8 Allergies and immune disease II.pdf#page=10|L8 Allergies and immune disease II, p.10]] [^11]: Original PDF page 11: [[L8 Allergies and immune disease II.pdf#page=11|L8 Allergies and immune disease II, p.11]] [^12]: Original PDF page 12: [[L8 Allergies and immune disease II.pdf#page=12|L8 Allergies and immune disease II, p.12]] [^13]: Original PDF page 13: [[L8 Allergies and immune disease II.pdf#page=13|L8 Allergies and immune disease II, p.13]] [^14]: Original PDF page 14: [[L8 Allergies and immune disease II.pdf#page=14|L8 Allergies and immune disease II, p.14]] [^15]: Original PDF page 15: [[L8 Allergies and immune disease II.pdf#page=15|L8 Allergies and immune disease II, p.15]] [^16]: Original PDF page 16: [[L8 Allergies and immune disease II.pdf#page=16|L8 Allergies and immune disease II, p.16]] [^17]: Original PDF page 17: [[L8 Allergies and immune disease II.pdf#page=17|L8 Allergies and immune disease II, p.17]] [^18]: Original PDF page 18: [[L8 Allergies and immune disease II.pdf#page=18|L8 Allergies and immune disease II, p.18]] [^19]: Original PDF page 19: [[L8 Allergies and immune disease II.pdf#page=19|L8 Allergies and immune disease II, p.19]] [^20]: Original PDF page 20: [[L8 Allergies and immune disease II.pdf#page=20|L8 Allergies and immune disease II, p.20]] [^21]: Original PDF page 21: [[L8 Allergies and immune disease II.pdf#page=21|L8 Allergies and immune disease II, p.21]] [^22]: Original PDF page 22: [[L8 Allergies and immune disease II.pdf#page=22|L8 Allergies and immune disease II, p.22]] [^23]: Original PDF page 23: [[L8 Allergies and immune disease II.pdf#page=23|L8 Allergies and immune disease II, p.23]] [^24]: Original PDF page 24: [[L8 Allergies and immune disease II.pdf#page=24|L8 Allergies and immune disease II, p.24]] [^25]: Original PDF page 25: [[L8 Allergies and immune disease II.pdf#page=25|L8 Allergies and immune disease II, p.25]] [^26]: Original PDF page 26: [[L8 Allergies and immune disease II.pdf#page=26|L8 Allergies and immune disease II, p.26]] [^27]: Original PDF page 27: [[L8 Allergies and immune disease II.pdf#page=27|L8 Allergies and immune disease II, p.27]] [^28]: Original PDF page 28: [[L8 Allergies and immune disease II.pdf#page=28|L8 Allergies and immune disease II, p.28]] [^29]: Original PDF page 29: [[L8 Allergies and immune disease II.pdf#page=29|L8 Allergies and immune disease II, p.29]] [^30]: Original PDF page 30: [[L8 Allergies and immune disease II.pdf#page=30|L8 Allergies and immune disease II, p.30]] [^31]: Original PDF page 31: [[L8 Allergies and immune disease II.pdf#page=31|L8 Allergies and immune disease II, p.31]] [^32]: Original PDF page 32: [[L8 Allergies and immune disease II.pdf#page=32|L8 Allergies and immune disease II, p.32]] [^33]: Original PDF page 33: [[L8 Allergies and immune disease II.pdf#page=33|L8 Allergies and immune disease II, p.33]] [^34]: Original PDF page 34: [[L8 Allergies and immune disease II.pdf#page=34|L8 Allergies and immune disease II, p.34]] [^35]: Original PDF page 35: [[L8 Allergies and immune disease II.pdf#page=35|L8 Allergies and immune disease II, p.35]] [^36]: Original PDF page 36: [[L8 Allergies and immune disease II.pdf#page=36|L8 Allergies and immune disease II, p.36]] [^37]: Original PDF page 37: [[L8 Allergies and immune disease II.pdf#page=37|L8 Allergies and immune disease II, p.37]] [^38]: Original PDF page 38: [[L8 Allergies and immune disease II.pdf#page=38|L8 Allergies and immune disease II, p.38]] [^39]: Original PDF page 39: [[L8 Allergies and immune disease II.pdf#page=39|L8 Allergies and immune disease II, p.39]] [^40]: Original PDF page 40: [[L8 Allergies and immune disease II.pdf#page=40|L8 Allergies and immune disease II, p.40]] [^41]: Original PDF page 41: [[L8 Allergies and immune disease II.pdf#page=41|L8 Allergies and immune disease II, p.41]] [^42]: Original PDF page 42: [[L8 Allergies and immune disease II.pdf#page=42|L8 Allergies and immune disease II, p.42]] [^43]: Original PDF page 43: [[L8 Allergies and immune disease II.pdf#page=43|L8 Allergies and immune disease II, p.43]] [^44]: Original PDF page 44: [[L8 Allergies and immune disease II.pdf#page=44|L8 Allergies and immune disease II, p.44]] [^45]: Original PDF page 45: [[L8 Allergies and immune disease II.pdf#page=45|L8 Allergies and immune disease II, p.45]] [^46]: Original PDF page 46: [[L8 Allergies and immune disease II.pdf#page=46|L8 Allergies and immune disease II, p.46]] [^47]: Original PDF page 47: [[L8 Allergies and immune disease II.pdf#page=47|L8 Allergies and immune disease II, p.47]] [^48]: Original PDF page 48: [[L8 Allergies and immune disease II.pdf#page=48|L8 Allergies and immune disease II, p.48]] [^49]: Original PDF page 49: [[L8 Allergies and immune disease II.pdf#page=49|L8 Allergies and immune disease II, p.49]] [^50]: Original PDF page 50: [[L8 Allergies and immune disease II.pdf#page=50|L8 Allergies and immune disease II, p.50]] [^51]: Original PDF page 51: [[L8 Allergies and immune disease II.pdf#page=51|L8 Allergies and immune disease II, p.51]] [^52]: Original PDF page 52: [[L8 Allergies and immune disease II.pdf#page=52|L8 Allergies and immune disease II, p.52]] [^53]: Original PDF page 53: [[L8 Allergies and immune disease II.pdf#page=53|L8 Allergies and immune disease II, p.53]] [^54]: Original PDF page 54: [[L8 Allergies and immune disease II.pdf#page=54|L8 Allergies and immune disease II, p.54]] [^55]: Original PDF page 55: [[L8 Allergies and immune disease II.pdf#page=55|L8 Allergies and immune disease II, p.55]] [^56]: Original PDF page 56: [[L8 Allergies and immune disease II.pdf#page=56|L8 Allergies and immune disease II, p.56]] [^57]: Original PDF page 57: [[L8 Allergies and immune disease II.pdf#page=57|L8 Allergies and immune disease II, p.57]] [^58]: Original PDF page 58: [[L8 Allergies and immune disease II.pdf#page=58|L8 Allergies and immune disease II, p.58]] [^59]: Original PDF page 59: [[L8 Allergies and immune disease II.pdf#page=59|L8 Allergies and immune disease II, p.59]] [^60]: Original PDF page 60: [[L8 Allergies and immune disease II.pdf#page=60|L8 Allergies and immune disease II, p.60]] [^61]: Original PDF page 61: [[L8 Allergies and immune disease II.pdf#page=61|L8 Allergies and immune disease II, p.61]] [^62]: Original PDF page 62: [[L8 Allergies and immune disease II.pdf#page=62|L8 Allergies and immune disease II, p.62]] [^63]: Original PDF page 63: [[L8 Allergies and immune disease II.pdf#page=63|L8 Allergies and immune disease II, p.63]] [^64]: Original PDF page 64: [[L8 Allergies and immune disease II.pdf#page=64|L8 Allergies and immune disease II, p.64]] [^65]: Original PDF page 65: [[L8 Allergies and immune disease II.pdf#page=65|L8 Allergies and immune disease II, p.65]] [^66]: Original PDF page 66: [[L8 Allergies and immune disease II.pdf#page=66|L8 Allergies and immune disease II, p.66]] [^67]: Original PDF page 67: [[L8 Allergies and immune disease II.pdf#page=67|L8 Allergies and immune disease II, p.67]] [^68]: Original PDF page 68: [[L8 Allergies and immune disease II.pdf#page=68|L8 Allergies and immune disease II, p.68]] [^69]: Original PDF page 69: [[L8 Allergies and immune disease II.pdf#page=69|L8 Allergies and immune disease II, p.69]] [^70]: Original PDF page 70: [[L8 Allergies and immune disease II.pdf#page=70|L8 Allergies and immune disease II, p.70]] [^71]: Original PDF page 71: [[L8 Allergies and immune disease II.pdf#page=71|L8 Allergies and immune disease II, p.71]] [^72]: Original PDF page 72: [[L8 Allergies and immune disease II.pdf#page=72|L8 Allergies and immune disease II, p.72]] [^73]: Original PDF page 73: [[L8 Allergies and immune disease II.pdf#page=73|L8 Allergies and immune disease II, p.73]] [^74]: Original PDF page 74: [[L8 Allergies and immune disease II.pdf#page=74|L8 Allergies and immune disease II, p.74]] [^75]: Original PDF page 75: [[L8 Allergies and immune disease II.pdf#page=75|L8 Allergies and immune disease II, p.75]] [^76]: Original PDF page 76: [[L8 Allergies and immune disease II.pdf#page=76|L8 Allergies and immune disease II, p.76]] [^77]: Original PDF page 77: [[L8 Allergies and immune disease II.pdf#page=77|L8 Allergies and immune disease II, p.77]] [^78]: Original PDF page 78: [[L8 Allergies and immune disease II.pdf#page=78|L8 Allergies and immune disease II, p.78]] [^79]: Original PDF page 79: [[L8 Allergies and immune disease II.pdf#page=79|L8 Allergies and immune disease II, p.79]] [^80]: Original PDF page 80: [[L8 Allergies and immune disease II.pdf#page=80|L8 Allergies and immune disease II, p.80]] [^81]: Original PDF page 81: [[L8 Allergies and immune disease II.pdf#page=81|L8 Allergies and immune disease II, p.81]] [^82]: Original PDF page 82: [[L8 Allergies and immune disease II.pdf#page=82|L8 Allergies and immune disease II, p.82]] [^83]: Original PDF page 83: [[L8 Allergies and immune disease II.pdf#page=83|L8 Allergies and immune disease II, p.83]] [^84]: Original PDF page 84: [[L8 Allergies and immune disease II.pdf#page=84|L8 Allergies and immune disease II, p.84]] [^85]: Original PDF page 85: [[L8 Allergies and immune disease II.pdf#page=85|L8 Allergies and immune disease II, p.85]] [^86]: Original PDF page 86: [[L8 Allergies and immune disease II.pdf#page=86|L8 Allergies and immune disease II, p.86]] [^87]: Original PDF page 87: [[L8 Allergies and immune disease II.pdf#page=87|L8 Allergies and immune disease II, p.87]] [^88]: Original PDF page 88: [[L8 Allergies and immune disease II.pdf#page=88|L8 Allergies and immune disease II, p.88]] [^89]: Original PDF page 89: [[L8 Allergies and immune disease II.pdf#page=89|L8 Allergies and immune disease II, p.89]] [^90]: Original PDF page 90: [[L8 Allergies and immune disease II.pdf#page=90|L8 Allergies and immune disease II, p.90]] [^91]: Original PDF page 91: [[L8 Allergies and immune disease II.pdf#page=91|L8 Allergies and immune disease II, p.91]] [^92]: Original PDF page 92: [[L8 Allergies and immune disease II.pdf#page=92|L8 Allergies and immune disease II, p.92]] [^93]: Original PDF page 93: [[L8 Allergies and immune disease II.pdf#page=93|L8 Allergies and immune disease II, p.93]] [^94]: Original PDF page 94: [[L8 Allergies and immune disease II.pdf#page=94|L8 Allergies and immune disease II, p.94]] [^95]: Original PDF page 95: [[L8 Allergies and immune disease II.pdf#page=95|L8 Allergies and immune disease II, p.95]] [^96]: Original PDF page 96: [[L8 Allergies and immune disease II.pdf#page=96|L8 Allergies and immune disease II, p.96]] [^97]: Original PDF page 97: [[L8 Allergies and immune disease II.pdf#page=97|L8 Allergies and immune disease II, p.97]] [^98]: Original PDF page 98: [[L8 Allergies and immune disease II.pdf#page=98|L8 Allergies and immune disease II, p.98]] [^99]: Original PDF page 99: [[L8 Allergies and immune disease II.pdf#page=99|L8 Allergies and immune disease II, p.99]] [^100]: Original PDF page 100: [[L8 Allergies and immune disease II.pdf#page=100|L8 Allergies and immune disease II, p.100]] [^101]: Original PDF page 101: [[L8 Allergies and immune disease II.pdf#page=101|L8 Allergies and immune disease II, p.101]]