BMS 250 WK3 Dermatitis (Derm Pt4) PDF

Pathophysiology of dermatitis BMS 250 Dr. Albert Iarz, ND, RMT  Learning Outcomes Compare the pathophysiology of dermatitis (allergic, atopic, contact, irritant, etc.) Describe the basic etiology and pathogenesis of atopic dermatitis Describe the basic etiology and pathogenesis of alle...

Pathophysiology of dermatitis BMS 250 Dr. Albert Iarz, ND, RMT  Learning Outcomes Compare the pathophysiology of dermatitis (allergic, atopic, contact, irritant, etc.) Describe the basic etiology and pathogenesis of atopic dermatitis Describe the basic etiology and pathogenesis of allergic contact dermatitis (type 4 delayed hypersensitivity reaction) Describe the basic etiology and pathogenesis of irritant dermatitis and its relationship to atopic dermatitis and contact dermatitis and relate to clinical features Describe the basic etiology and pathogenesis of seborrheic dermatitis and relate to clinical features  Atopic Dermatitis Overview: AKA: atopic eczema or AD A complex familial transmitted skin disease caused by interactions among genetic, immune, and environmental risk factors a chronic inflammatory skin disease primarily beginning in - childhood with a variable natural course. - Itch is the hallmark symptom of the disease, often unrelenting in severe cases, and leads to sleep disturbance and excoriated, - - infection-prone skin. - Patients often additionally have atopic co-morbidities such as * allergic asthma and allergic rhinitis c a and experience a significantly impaired quality of life. Atopic Dermatitis  Atopic Dermatitis Has a prevalence peak of 15% to 20% in early childhood in industrialized countries. Has variable rates of remission, with many patients continuing or recurring with symptoms into adulthood. A chronic or chronically relapsing disorder with major features of: 33 Pruritus = itching · Eczematous dermatitis (acute, subacute, or chronic) Facial and extensor involvement in infancy Flexural eczema or lichenification in children and adults Commonly associated with the following: Personal or family history of atopy (allergic rhinitis, asthma, atopic dermatitis) Xerosis or skin barrier dysfunction Immunoglobulin E reactivity -  Atopic Dermatitis Overview Pathogenesis driven by: skin barrier defects (most importantly in the 0xFLG gene) environmental effects alterations in immunologic responses in T cells, antigen processing, inflammatory cytokines, host defense proteins, allergen sensitivity, and infection.  Atopic Dermatitis Types Eczema Contact Dermatitis Seborrheic Dermatitis Dyshidrotic Eczema (FYI) Neurodermatitis (FYI) Nummular Eczema (FYI) Stasis Dermatitis (FYI)  AD Etiology Prevalence has tripled since the 1960s. Affects 10–20% of children in industrialized countries. 3–7% prevalence in adults (U.S., Germany, Japan). - Female predominance: 1.3:1 (female-to-male).  AD Clinical Features - Acute Lesions characterized by: Appearance: Erythematous papulovesicles (small red bumps or blisters). Surface Changes: Often accompanied by pinpoint crusting or frank weeping due to exudation. Symptoms: Highly pruritic (itchy), leading to scratching and further irritation.  AD Clinical Features Subacute or Chronic Lesions - Appearance: Exhibits dry, scaly plaques. Surface Changes: May show excoriation (scratches from itching) and lichenification (thickened skin with exaggerated skin lines due to chronic rubbing or scratching). Symptoms: Persistent pruritus, with less erythema compared to acute lesions.  AD Clinical Features Patients may present with a single stage of lesions or a mixture of acute and chronic lesions. Lesions often occur - simultaneously - in multiple areas or within the same lesion. Indistinguishable clinically or histologically from other eczematous conditions, such as: [3 Allergic contact dermatitis Nummular dermatitis  AD Clinical Features Patients with darker skin tones often present with follicular accentuation Inflammation of hair follicles flat-topped papules in lichenified areas and a tendency toward hyperpigmentation in inflamed areas Rarely, patients may also experience a vitiligo- like depigmentation  AD Clinical Features The distribution of eczematous lesions vary according to the patient’s age and disease activity. During infancy, generally more acute and primarily involves the face, the scalp, and the extensor surfaces of the extremities e The diaper area is usually spared - AD Clinical Features  AD Clinical Features In older children and in those who have long- standing skin disease the patient develops the chronic form of AD with lichenification and localization of the rash to the * flexural folds of the extremities AD may subside as the patient grows older, leaving an adult with skin that is prone to itching and -access inflammation when exposed to exogenous irritants. - -  AD Clinical Features -Chronic hand eczema may be the primary manifestation of AD in many Dry, scaly skin > adults At least one third of patients will have clinical features of filaggrin deficiency such as ichthyosis vulgaris, - keratosis pilaris, and hyperlinear ~ palms. Small scaly bumps on skin where there are hair follicles (chicken skin) These clinical features are associated with genetic defects encoding the filaggrin protein and can identify patients who have a more severe disease course and allergic co-morbidities. AD Clinical Features  AD Clinical Features Dry, pale patches on skin Chicken skin Dry, scaly skin Cornea thins & gradually bulges outward into a cone shape  Atopic Dermatitis People who suffer with atopic dermatitis can have Comorbidities -They show signs of T helper 2 (Th2) immune activation, including high levels of total and specific serum IgE, eosinophilia, and - a predisposition toward allergic comorbidities There is a psychosocial impact (anxiety, Producing too many depression,etc eosinophils  Atopic Dermatitis Complications Bacterial, Viral, Fungal infections Ocular Issues (eyelid dermatitis, etc) Hand dermatitis Exfoliative dermatitis This is associated with generalized redness, scaling, weeping, crusting, systemic toxicity, lymphadenopathy, and fever. Although this complication is rare, - it is potentially -D life threatening  AD & Skin Barrier There is a decrease in skin barrier function caused by: The downregulation of cornified envelope genes (eg, keratin, filaggrin, and loricrin) Weakens stratum corneum - increased vulnerability to allergens, irritants & u pathogens Reduced ceramide levels Critical lipids in skin barrier - reduction leads to increased water loss ↑ Increased endogenous proteolytic enzyme activity *A Enhanced transepidermal water loss. Hallmark of AD - dryness = itchy & inflammation The addition of soap and detergents to the skin raises its pH, thereby increasing activity of - endogenous proteases, leading to further P breakdownarenof epidermal barrier function.  AD & Skin Barrier The epidermal barrier may also be damaged by E scratching exposure to exogenous proteases from house dust mites, and S. aureus. 3 This is worsened by the lack of certain endogenous protease inhibitors in atopic skin. These epidermal changes likely contribute to increased allergen absorption into the skin and microbial colonization. Because epicutaneous sensitization to allergen results in higher Ja level allergic immune responses, decreased skin barrier function [ could act as a site for allergen sensitization and predispose such children to the development of food allergy and respiratory allergy.  AD & Genetics Many genes have been associated with AD However, of these genes, there is a loss of function mutations that involve the epidermal Ca barrier protein FILAGGRIN Filaggrin gene is found on chromosome 1q21 * i s This chromosome contains other genes that are all involved in the epidermal differentiation complex (EDC) This complex is expressed during terminal differentiation of the epidermis  AD & Genetics Mutations impair skin barrier function, a key factor in AD pathogenesis. Impaired barrier leads to: Increased transepidermal water loss (TEWL) Increased attachment and entry of allergens and chemicals These changes trigger inflammatory skin responses.  AD & Genetics It is important to note that filaggrin mutations and likely other mutations affecting the skin barrier can occur in normal healthy individuals Only a minority of individuals with AD have filaggrin gene mutations. This suggests that factors other than skin barrier - gene mutations are also required for the - development of AD. -  Immunopatholgy of AD Based on clinical appearance and duration of illness, AD skin can be characterized as; non-lesional AD acute AD lesions (3 or fewer days after onset), chronic skin lesions (>3 days’ duration)  Immunopatholgy of AD Nonlesional AD Not entirely normal: 3 Mild epidermal hyperplasia (thickening of the epidermis). · Sparse perivascular T-cell infiltrate in the dermis.  Immunopatholgy of AD Acute Lesions Epidermal spongiosis: Intercellular edema in the - epidermis, leading to disruption of keratinocyte - - cohesion. - T-Cell Activation: Increased infiltration of activated memory T-cells with skin-homing cutaneous lymphocyte-associated antigen (CLA). Other Immune Cells: Rare presence of eosinophils, basophils, and neutrophils. Mast cells: Found in various stages of degranulation, contributing to inflammation and itch. - -  Immunopatholgy of AD Both nonlesional and lesional AD skin feature: Dendritic antigen-presenting cells: Langerhans cells (LCs) Inflammatory dendritic epidermal cells (IDECs) Macrophages Key Difference: * In nonlesional AD, dendritic cells exhibit fewer surface-bound immunoglobulin E (IgE) molecules compared to lesional skin D A  Immunopatholgy of AD Key Features of Chronic Lichenified Lesions: Hyperplastic epidermis with elongation of rete ridges. Prominent hyperkeratosis (thickened keratin layer). - Minimal spongiosis (reduced intercellular edema). - Immune Cell Characteristics: Increased IgE-bearing Langerhans cells (LCs) in the epidermis. Macrophages dominate the dermal mononuclear cell infiltrate. Increased mast cells, but fully granulated (non- A - degranulated).  Immunopatholgy of AD Neutrophils: Absent in AD skin lesions, even with increased Staphylococcus aureus colonization or infection. Eosinophils: Increased in chronic AD skin lesions. Contribute to allergic inflammation through: Cytokine and mediator secretion, amplifying inflammation. Production of reactive oxygen intermediates, causing tissue injury. Release of toxic granule proteins, further damaging the skin barrier.  AD & Inflammation Atopic dermatitis (AD) skin inflammation is orchestrated by the local expression of proinflammatory cytokines, driving immune dysregulation and skin barrier dysfunction. Key Differences in AD Epidermis vs Normal Epidermis: Thymic Stromal Lymphopoietin (TSLP): G Highly expressed in AD skin. Activates dendritic cells, which promote Th2 immune responses, enhancing inflammation. Interleukin-33 (IL-33): * Released by damaged or stressed keratinocytes. Potentiates type 2 immunity, amplifying allergic inflammation. - Comparison with Normal Skin: * [ Normal keratinocytes lack significant levels of TSLP and IL-33, highlighting their role as key drivers of AD inflammation.  AD & Inflammation TSLP and IL-33: Secreted by epithelial cells. Induce dendritic cells to drive Th0 cells into the Th2 differentiation pathway. Cytokines in Nonlesional and Acute AD: * Key cytokines: IL-4, IL-5, IL-13, IL-25, IL-31, IL-33. A Predominantly expressed in nonlesional and acute AD lesions. Type 2 Cytokines: ↳ Present in all stages of AD. Secreted by multiple cell types: Innate lymphoid type 2 cells. Mast cells. Basophils.  AD & Inflammation Redundancy in Allergic Inflammation: Multiple cell types produce overlapping cytokines, creating significant redundancy in the inflammatory process. Treatment Strategy: Cytokine targeting is more effective than targeting specific cells in managing atopic dermatitis (AD). Key Functions of Type 2 Cytokines: In animal models, they replicate clinical features of AD, including: # Elevated IgE responses. Eosinophilia. Skin barrier dysfunction. Allergic skin inflammation. Itching.  AD & Inflammation Beyond Th2 Pathways: Other cytokine pathways, including IL-22–IL-17, play a significant role in AD. These cytokines, along with IL-4 and IL-13, can inhibit: Terminal keratinocyte differentiation. Filaggrin expression, contributing to skin barrier dysfunction. IL-23 and its Role: Dendritic cell–derived IL-23 enhances IL-22–IL-17 differentiation. IL-4 and IL-13 can further enhance IL-23 production by dendritic cells.  AD & Inflammation Therapeutic Insights: Blockade of the IL-4 and IL-13 pathways: Improves AD symptoms. Reduces IL-23 and IL-17 expression in AD skin.  AD & Inflammation Transition from Acute to Chronic AD: Increased Th1 cytokines: INF-γ: Potentiates - skin inflammation in chronic AD. Elevated IL-5: Promotes eosinophil development and survival, contributing to inflammation. Role of TSLP in Early AD: A birth cohort study showed TSLP can be detected in at-risk infants before AD onset. * Suggests the TSLP–Th2–ILC2 pathway is critical in initiating AD. &  AD & Chemokines CTACK (CCL27): Highly upregulated in atopic dermatitis (AD). Attracts - skin-homing CLA+ CCR10+ T cells into the skin. CCR4 and CCL17: CCR4, expressed on skin-homing CLA+ T cells, binds to CCL17 on cutaneous venules. Facilitates targeted T-cell migration into inflamed skin. Selective Th2 Recruitment: CCR4-expressing Th2 cells are recruited by: [3 Macrophage-derived chemokine (MDC). Thymus and activation-regulated cytokine (TARC). Both MDC and TARC are elevated in AD.  AD & Chemokines Severity of AD: Correlates with levels of thymus and activation-regulated cytokine (TARC). Th1 Cell Migration in Chronic AD: Driven by upregulated keratinocyte chemokines: 53 Fractalkine IFN-γ–inducible protein 10 (IP-10) Monokine induced by IFN-γ (MIG) Immune Cell Infiltration in Acute and Chronic AD: Elevated CC chemokines: Macrophage chemoattractant protein-4 (MCP-4) Eotaxin RANTES (regulated on activation, normal T-cell expressed and secreted) Recruit macrophages, eosinophils, and T cells into skin lesions. IMMUNE EFFECTS ON EPITHELIAL DIFFERENTIATION COMPLEX To review The dry skin increased transepidermal water loss in individuals with AD reflect the underlying skin barrier dysfunction and loss of natural moisturizing factors that play an important role in the pathogenesis of AD. Only a minority of patients, however, have FLG null - mutations. Other genetic variants in the EDC and tight junctions are even rarer. E 3 The majority of patients with AD likely have immune-mediated reduction in epidermal IMMUNE EFFECTS ON EPITHELIAL DIFFERENTIATION COMPLEX Effects of Reduced Epidermal Differentiation: Decreased production of: b Epidermal structural proteins. Filaggrin breakdown products. Epidermal lipids. & Antimicrobial peptides (AMPs). Key Cytokines Downregulating Filaggrin Expression: TSLP, IL-4, and IL-13: Most potent inhibitors of filaggrin production in keratinocytes. Synergistic Cytokines: IL-17, IL-22, IL-25, and IL-33: Act synergistically with IL-4 and IL-13 to further suppress epidermal protein and lipid expression. IMMUNE EFFECTS ON EPITHELIAL DIFFERENTIATION COMPLEX This combination of events along with activation of proteases and lipases 53 creates defective epidermal barrier function and alters epidermal acidification and loss of moisturization thereby contributing to enhanced allergen and microbial penetration met by the host immune response and clinical appearance of AD. Why so itchy?  Basis of Pruritus in AD O Pruritus is a prominent feature of AD Manifested as cutaneous hyper-reactivity and scratching after exposure to allergens, changes in humidity, excessive sweating, and low concentrations of irritants. Control of pruritus is important because mechanical injury from scratching can induce pro- inflammatory cytokine and chemokine release, leading to a vicious scratch–itch cycle, perpetuating - the AD skin rash.  Basis of Pruritus in AD The mechanisms of pruritus in AD are poorly understood. Allergen-induced release of histamine from skin - mast cells is not an exclusive cause of pruritus because H1 antihistamines do not appear to control the itch of Treatments with topical corticosteroids (TCs) and calcineurin inhibitors are effective at reducing pruritus and this suggests that histamine cells play - an important role in pruritus. -  Basis of Pruritus in AD Other Molecules that have been implicated in pruritus include T Cell–Derived Cytokines: IL-31: A key pruritogenic cytokine released by activated T cells. Acts directly on sensory nerves to induce itching. - Stress-Induced Neuropeptides: Examples: Substance P, CGRP (calcitonin gene-related peptide). Amplify the itch response by sensitizing nerve endings in the - - skin. Proteases: Proteases can act on protease-activated receptors (PARs): G PAR-2 is linked to enhanced nerve activation and itch. - Protease activity is elevated in inflamed AD skin.  Basis of Pruritus in AD Other Molecules that have been implicated in pruritus include T Cell–Derived Cytokines: Eicosanoids: Lipid mediators derived from arachidonic acid (e.g., prostaglandins, leukotrienes). Contribute to inflammation and neuronal sensitization in the skin. Eosinophil-Derived Proteins: Proteins such as major basic protein (MBP) and eosinophil-derived neurotoxin (EDN). Can damage nerves and amplify pruritus in AD. -  Allergic Contact Dermatitis Definition: Allergic contact dermatitis (ACD) is a cell-mediated hypersensitivity reaction: Type IV (delayed-type) hypersensitivity. - Triggered by skin contact with an environmental allergen. Mechanism: Prior Sensitization is required: The immune system must first be exposed to the allergen to develop a response. ---- Allergens, often haptens, bind to skin proteins to form complexes that are recognized as foreign. Sensitization leads to activation of T cells, which mediate the inflammatory response upon subsequent exposure. Clinical Presentation: ↳ The hallmark of ACD is eczematous dermatitis: ~ Symptoms include redness, itching, swelling, and vesicle formation at the site of contact. Chronic exposure can lead to lichenification and scaling. -Thickened leathery skin  Allergic Contact Dermatitis Overview Continued The acute phase is characterized by 24 pruritus erythema edema vesicles Which are usually confined to the area of direct exposure.  Allergic Contact Dermatitis Chronic Presentation: Repeated exposure to allergens can cause lichenified erythematous plaques with: [ J Hyperkeratosis. Fissuring. Pigmentary changes. Lesions may spread beyond areas of direct exposure. Key Symptoms: Itch and swelling are hallmark features and provide clues to an allergic etiology. Diagnosis: * Patch testing is the diagnostic gold standard for identifying causal allergens. A Recommended for patients with persistent or recurrent dermatitis when ACD is suspected. Treatment: Allergen avoidance is the cornerstone of management. Patient education is critical: Identify and avoid allergens and related substances. Provide suitable alternative products. Allergic Contact Dermatitis Allergic Contact Dermatitis  ACD and Clinical Features The classic presentation of ACD is: a pruritic, eczematous dermatitis initially localized to the primary site of allergen exposure. Geometric, linear, or focal patterns of involvement are suggestive of an exogenous etiology. For example, ACD from poison ivy typically presents as a linear or streaky array of erythematous papules and vesicles. Because the mechanism of allergen exposure influences the clinical presentation, relevant historic data gathered from thoughtful questioning may prove as useful as the distribution of the lesions.  ACD morphology Changes depending on the stage of the disease Acute lesions are: Edematous Erythma Vesicle formation or papular formation depending the strength of allergen Subacute lesions are: [3 Ruptured vesicles that ooze Scaly juicy papules associated with weeping and crusting dominate  ACD morphology Chronic Lesions: [] scaling fissuring lichenification. However, A key symptom for ACD is pruritus, which seems to occur more typically than a symptom of a burning sensation.  ACD Pathogensis Mechanism of Allergic Contact Dermatitis (ACD) Type IV Hypersensitivity: ACD is a classic cell-mediated, delayed hypersensitivity reaction (Type IV). Triggered by exposure to an environmental allergen in genetically susceptible individuals. Clinical Features: Erythema, edema, and papulovesiculation. Typically occurs in areas of direct contact with the allergen. Pruritus (itching) is a major symptom.  ACD Pathogensis Mechanism of Allergic Contact Dermatitis (ACD) Sensitization Phase: Initial contact with the allergen leads to immune activation and the development of immunologic memory. Requires sufficient exposure to the sensitizing chemical. Elicitation Phase: Subsequent re-exposure triggers a complex inflammatory reaction, even with minute quantities of the allergen. Role of Haptens in Allergic Contact Dermatitis (ACD) Haptens: Small, lipophilic molecules with a low molecular weight (