Immunology Key Concepts

• Diseases of the immune system and skin involve interactions between the immune system and skin conditions.
• Immunopathology knowledge is essential for understanding these diseases.

Outline of Topics

• Normal immune response fundamentals.
• Immune system cells.
• Lymphocyte activation and adaptive responses.
• Hypersensitivity reactions.
• Autoimmune diseases.
• Skin anatomy and function, inflammatory dermatoses, infectious diseases, and neoplasia.

Normal Immune System

• The objective is to protect against infections.
• Immune system malfunctions can lead to tissue injury and disease, known as hypersensitivity disorders.
• Immune system defects result in immunodeficiency diseases.

Normal Immune Response

• Innate immunity is mediated by always-available cells and proteins.
• Adaptive immunity is typically inactive but generates strong mechanisms to neutralize and remove pathogens.
• Adaptive immunity takes 3-7 days to become fully active.

Innate Immunity

• Epithelial barriers
• These recognize infectious agents and dead cell substances.
• Phagocytic cells
• Dendritic cells
• NK cells
• Innate lymphoid cells
• Plasma proteins, including the complement system

Receptors of innate immunity

• PRRs recognize PAMPs and DAMPs, located in cellular compartments for pathogen detection.
• Toll-like receptors.
• NOD-like receptors
• Inflammasomes
• Other microbial product receptors.

Reactions of innate immunity

• The innate immune system provides mainly two reactions for host defense.
• Inflammation mediated by mediators.
• Antiviral defense through type I IFNs.
• The signals generated stimulate the adaptive immune response.

Adaptive Immunity

• Involves lymphocytes and antibodies.
• Humoral immunity is mediated by antibodies (Abs).
• Cellular immunity is mediated by T-cells.

Adaptive Immunity Function and Dysfunction

• Protection against infections and abnormal cells.
• Dysfunction: adverse immune reactions like hypersensitivity and autoimmune diseases.
• Unwanted reactions: transplant rejection.
• Decreased immunity: immunodeficiencies.

Cells of the Adaptive Immune System: T Lymphocytes

• T-helper cells (CD4+) and cytotoxic T lymphocytes (CD8+).
• T cells recognize peptide antigens presented by MHC molecules.
• T cells cannot recognize free or circulating antigens.

CD4+ T-cells: Help and memory

• Antigen binding occurs through TCR that binds to antigen presented by class II MHC.
• Costimulatory molecule engagement is necessary for T-cell activation.
• Activated T cells differentiate into T-helper cells (Th1, Th2, Th17).
• Some differentiate into T-memory cells.

CD8+ T cells: Effector cells

• Antigen binding occurs through the TCR that binds to antigen presented by class I MHC.
• Activation leads to cytotoxic response, including apoptosis in a target cell.

B Lymphocytes

• Produce antibodies, which mediate humoral immunity.
• B lymphocytes do not require MHC.
• B lymphocytes recognize many chemical structures.
• They differentiate into plasma cells upon stimulation.
• IgG, IgM, and IgA are the main circulating antibodies.

Antigen presenting cells (APCs)

• These are important for capturing microbes.
• They express receptors for microbe capture and response.
• APCs migrate to T cell zones in lymphoid organs and express high levels of MHC.

Overview of Lymphocyte Activation and Adaptive Immune Responses

• Proceeds in steps: antigen recognition, activation, proliferation and differentiation, elimination of antigen, and decline of response.

Cell-Mediated Immunity

• Naive T cells activate within secondary lymphoid organs to become effector cells.
• CD4+ T cells become effector cells that secrete cytokines.
• Activated CD8+ T cells become cytotoxic T cells (CTLs).

Humoral immunity: B Lymphocytes

• Two main activation pathways: T-cell dependent and T-cell independent.
• High-affinity antibodies bind to microbes.
• IgG antibodies coat microbes for phagocytosis.
• IgG and IgM activate the complement system.
• IgA neutralizes microbes in mucosal tissues, while IgE activates mast cells against helminths.

Hypersensitivity

• This is immunologically mediated tissue injury.
• It involves an injurious immune response to exogenous or endogenous antigens, with inadequate response control.

Causes of Hypersensitivity Reactions

• Autoimmunity (self-antigens).
• Reactions against microbes and environmental antigens (allergens).
• Tissue injury stems from mechanisms that typically eliminate infectious pathogens.

Classification of Hypersensitivity Reactions

• Immediate (Type I): Allergy; Ab mediated
• Antibody-mediated (Type II): Ab mediated.
• Immune complex-mediated (Type III):, Ab mediated.
• T-cell-mediated (Type IV).

Immediate (Type 1) Hypersensitivity

• Develops rapidly.
• Involves Th2 cell activation, IgE antibody production, and mast cell sensitization.
• Re-exposure leads to mast cell activation and mediator release, including vasoactive amines, lipid mediators, and cytokines.
• Consequences: vascular dilation, edema, and smooth muscle contraction.
• Anaphylaxis, allergies, and asthma are typical examples.

Clinical and Pathologic Manifestations of Allergic Diseases

• Include an immediate response (5-30 minutes) and a late-phase response (2-8 hours later).
• They can be local, like allergies, or systemic, like anaphylaxis.

Antibody-Mediated Diseases (Type II Hypersensitivity)

• These are caused by antibodies against cell surface or tissue antigens.
• They mainly cause opsonization and phagocytosis, inflammation, or cellular dysfunction.

Antibody-Mediated Diseases (Type II Hypersensitivity): Graves disease

• Diffuse hyperplasia of the thyroid, with hyperthyroidism.
• Hallmark symptoms include: elevated T3 and T4 and low TSH levels.
• Characterized by ophthalmopathy and pretibial myxedema.

Immune Complex-Mediated Diseases (Type III Hypersensitivity)

• Characterized by the formation of antigen-antibody complexes in circulation.
• Deposition in blood vessels.
• This leads to complement activation and acute inflammation.

Antigen Source in Type III Hypersensitivity

• Injected foreign proteins.
• Infectious agent products.
• Endogenous antigens.
• Pathogenesis involves forming immune complexes.

T-Cell-Mediated (Type IV) Hypersensitivity

• Pathogenic: autoimmune disorders.
• Pathogenic: reactions to environmental chemicals.
• Pathogenic: reactions to persistent microbes.

T-cell-mediated hypersensitivity.

• CD4+ T cell-mediated inflammation with Th1 and Th17 effector cells.
• CD8+ T cell-mediated cytotoxicity involving cell killing and tissue injury.
• This is known as 'delayed type'.

T-cell-mediated hypersensitivity, 'delayed type'

• Occurs in tuberculin reactions, rheumatoid arthritis, and drug reactions.
• Prolonged DTH reactions in tuberculosis infection.

Skin structure

• 5 kg, 2 m².
• Thin epidermis (0.05-0.1 mm thick) with keratinocytes.
• Thicker dermis (0.5 to >5 mm) with collagen and elastin.
• Subcutis.
• Includes the basal layer, spinous layer, granular layer, and stratum corneum.

Skin Function:

• Physical barrier against intruders.
• Protection from UV damage.
• Prevention of water loss and thermoregulation.
• Contains fat for calorie reserve, trauma protection, and endocrine function.
• Has hair with social and psychological value.
• Production of vitamin D.

Inflammatory Dermatoses

• Numerous
• Microscopy is as important as the clinical picture. -Microscopy is as important as the clinical picture.
• Tissue reaction patterns include spongiotic, psoriasiform, interface, perivascular, and vesiculobullous.

Urticaria ('Hives')

• Involves a Type 1 hypersensitivity reaction and mast cell degranulation.
• The histological findings are often subtle

Eczema

• Can be atopic, contact-allergic, drug-related, photoeczematous, or irritant-induced.

Erythema Multiforme (EM)

• A hypersensitivity reaction to infections or drugs.
• Characterized by interface dermatitis with CD8+ T cells.
• Should be differentiated from Stevens-Johnson syndrome/toxic epidermal necrolysis.

Psoriasis

• A T cell-mediated inflammatory disease.
• Presumed: autoimmune.
• Associated with Koebner phenomenon and psoriatic arthritis.

Lichen Planus

• 5 Ps: pruritic, purple, polygonal, planar papules, and plaques.
• CD8+ T cell-mediated response to unknown antigens.
• Symmetrical on extremities, often with oral mucosal involvement (~70%).

Blistering (Bullous) Disorders

• Characterized by blister formation and specific levels within the skin.

Blister Levels

• Subcorneal
• Suprabasal
• Subepidermal

Bullous Disorders

• Pemphigus vulgaris and foliaceus.
• Paraneoplastic pemphigus.
• Bullous pemphigoid.
• Dermatitis herpetiformis.
• Involves Type II hypersensitivity reactions and IgG Abs against desmoglein 3.

Infectious Dermatoses

• Bacterial
• Fungal
• Viral
• Needs fungal infection ruled out

Tumors of the Skin

• Benign: seborrheic keratosis.
• Premalignant: actinic keratosis, squamous cell carcinoma in situ (Bowen's disease).
• Malignant: epidermal or melanocytic.

Melanocytic Proliferations

• Melanocytic nevi
• Melanocytic nevi: melanocytic nevi - pathogenesis
• Melanocytic nevi, melanocytes undergo: Gain of function mutation in BRAF or RAS leading to Increased proliferation Accumulation of p16/INK4a (oncogene-induced senescence), & growth arrest

Malignant Tumors:

• Basal cell carcinoma (basal)
• Squamous cell carcinoma (squamous)

Melanomas

• Melanoma is often caused by UV damage.
• Melanoma incidence is on the rise.
• Melanoma appears in exposed skin and geographic locales.
• Characterized by asymmetry, irregular borders, color variations, diameter, and evolution.

Explore the critical functions of the immune system, differentiating between innate and adaptive immunity. Review roles of phagocytic cells and Pattern Recognition Receptors (PRRs), and problems in adaptive immunity. Types II and III hypersensitivity are covered.