Dermal System Lecture Notes PDF

Dermal system-Dr. Vishy Venketaraman Slide#1-25: OBJECTIVES: 1. Describe the characteristics of immune cells in the epidermis and dermis and how they contribute to immune defenses, hypersensitivity and autoimmune reactions. 2. Giving examples, describe...

Dermal system-Dr. Vishy Venketaraman Slide#1-25: OBJECTIVES: 1. Describe the characteristics of immune cells in the epidermis and dermis and how they contribute to immune defenses, hypersensitivity and autoimmune reactions. 2. Giving examples, describe the characteristics of type I, II, III and IV hypersensitivity reactions in skin. 3. Describe the pathogenesis of Atopic dermatitis (type I), Urticaria (type I), Pemphigus vulgaris (type II), Pemphigus foliaceus (type II), Bullous pemphigoid disease (type II), Linear IgA dermatosis (type II), Dermatitis herpetiformis(type III), Systemic lupus erythematosus(type III), Contact dermatitis (type IV), Erythema multiforme-minor (type IV), Erythema multiforme-major (type IV), Steven- Johnson syndrome(type IV) , Toxic epidermal necrolysis (type IV), Scleroderma and Psoriasis (autoimmune diseases). Skin and innate immunity: The most important role of the skin may, however, be the protection against environmental threats such as microbes, UV light, or chemicals. Skin is highly impermeable and prevents the organisms from gaining access to internal organs. The outer layer of dead cells in the skin gets sloughed eliminating organisms that are bound to the skin. Skin contains sebaceous glands that secrete sebum which maintains a low pH (5.5) thereby preventing colonization of bacteria. Skin also secretes lysozyme and antimicrobial peptides like cathelicidins and defensins. Lysozyme degrades peptidoglycan layer on the surface of the Gram-positive bacteria. Skin layers: Skin is composed of the outermost epidermis and inner dermis. Epidermis is made of four layers. The outermost layer of epidermis is called stratum corneum and is made of dead cells and is formed by keratinocytes in the lower three layers of epidermis. The other layers of skin in descending order include stratum granulosum, stratum spinosum and stratum basale. The dermis is made of blood vessels, nerves, collagen fibers and cells such as dendritic cells fibroblasts and mast cells. Keratinocytes (KCs), dendritic cells (DCs), and mast cells (MCs), are resident skin cells that contribute in many ways to optimal innate defense mechanisms. Cells in the skin: Keratinocytes: One of the essential functions of the skin as a whole, and the epidermis and epidermal KCs in particular, is to provide an effective barrier against physical, chemical, and biological environmental factors. Epidermal KCs are specialized in many ways to exert their crucial role as outpost of the innate defense system. In the upper layer of the epidermis the cells build a physical barrier, the stratum corneum, against penetration of microbes and allergens. In the stratum corneum, KCs are tightly locked together by desmosomes and are embedded in a hydrophobic intercellular matrix. Desmosomes are composed of proteins such as Desmoglein 3 and Desmoglein 1 that function as glue tightly locking the keratinocytes. Desmoglein 3 is present in the basal part of epidermis whereas Desmoglein 1 is present in the suprabasal region. KCs in the basal part of epidermis are connected to the basement membrane by structures called hemidesmosomes. Hemidesmosomes contain proteins called bullous pemphigoid antigens (BP) which are integrin proteins. There are two types of bullous 1  Dermal system-Dr. Vishy Venketaraman pemphigoid antigens BPAg1 and BPAg2. BPAg1 has a molecular weight of 230 kD and BPAg2 has a molecular weight of 180 kD. Filaggrin is a protein involved in the terminal differentiation of the epidermis. Skin barrier dysfunction not only increases the risk of microbial infections but is also associated with increased risk for allergic diseases. For example, mutations in filaggrin, a protein involved in the terminal differentiation of the epidermis, was found to be associated with diseases such as atopic dermatitis and allergic asthma as well as with increased rates of sensitization to allergens, for example nickel. Keratinocytes play an important role in innate immunity. Epidermal KCs are also able to produce and release a vast variety of antimicrobial peptides, thereby building an effective chemical shield against microbes. Activation of KCs, for example via toll-like receptors (TLR) or UV light, enhances the production of antimicrobial peptides and can additionally induce the production and secretion of other mediators, including proinflammatory peptides such as endothelin-1 and various cytokines which can contribute to optimal innate immune responses either directly or through interaction with other cells. Dendritic cells: If the epidermal barrier is disrupted, pathogens as well as allergens make contact with other resident innate immune cells in the skin. Dendritic cells have extended membrane filaments like dendrites and hence called dendritic cells. Dendritic cells can phagocytose as well as pinocytose. DCs are professional antigen presenting cells, which are ideally located to detect any skin invading pathogen and allergen. DCs are a heterogeneous population of immune cells, which are thought to exert different functions depending on their origin, their state of activation and their location. In the skin, DC subsets are classified as Langerhans cells (epidermal DCs). The major function of DCs is the initiation of adaptive immune responses, for example the presentation of microbial antigens to T cells and the modulation of T cell differentiation. In the skin, Langerhans cells as well as dermal DCs can take up antigen, process it into fragments and migrate to regional lymph nodes where they present the antigen to cells of the adaptive immune system. The antigen processed by DCs can either be of microbial origin leading to antimicrobial adaptive immune responses or it can be an allergen which may lead to immediate or delayed hypersensitivity type allergic reactivity. While these general mechanisms are well characterized, current areas of interest are the contribution of innate mechanisms (e.g. toll-like receptors) to the development of DC- mediated sensitization and the exact function of DC subsets in the presentation of antigens. DCs process complex protein antigens and present the antigenic peptides along with MHC class I or II molecules for recognition by T cells. CD4+T cells recognize processed antigenic peptides that are displayed on the cell surface of DCs in association with MHC Class II molecules. Whereas CD8+T cells recognize processed antigenic peptides that are displayed on the cell surface of DCs in association with MHC class I. Processing of antigens by DCs for recognition by CD4 and CD8 T cell cells occurs in different compartments. Usually an extracellular protein antigen is phagocytosed by DCs and is processed within endosomal compartment where the complex protein is broken down and the antigenic peptide is associated with MHC class II molecules and the entire complex is transported to the cell surface of DCs for CD4 recognition. During viral infection, the secreted viral proteins from the intracellular virus processed inside proteasomes of DCs. The processed antigenic peptide is then transported to the rough endoplasmic reticulum by a transporter protein called 2  Dermal system-Dr. Vishy Venketaraman TAP protein. Inside the rough endoplasmic reticulum, the antigenic peptide associates with MHC Class I molecules and this processed antigen-MHC Class I complex is transported to the cell surface of DCs for recognition by CD8+T cells. During antigen recognition process, T cell receptor binds to the processed antigenic peptide on the cell surface DC. Concomitantly, the CD4 molecules on helper T cells bind to the non-peptide binding region of the MHC class II on DCs and CD8 molecules on the cytotoxic T cells bind to non-peptide end of MHC Class I on the cell surface of the DCs. This binding often referred to as signal I is critical but not completely sufficient to induce T cell activation. Binding of additional co-stimulatory molecules on cell surface of DCs to the corresponding ligands on T cells is also required for T cell stimulation. DCs express surface co-stimulatory markers such as CD80, CD86, HLA-DR and ICAM that bind to the corresponding ligands on the cell surface of T cells to induce T cell activation and this referred to as signal II. CD80, CD86 on cell surface of DCs bind to CD28 on T cells and intracellular adhesion molecule (ICAM) on DCs bind to leukocyte function associated antigen (LFA) on the cell surface of T cells to induce T cell activation and response. CD4+T cells or helper cells are divided into two main subsets such as T helper 1 (Th1) and T helper 2 (Th2) based on their cytokine production. The differentiation of CD4T cells to Th1 and Th2 subset is DEPENDENT on the polarizing cytokines (this is signal 3) produced by the DCs during antigen presentation. Interleukin 12 (IL-12) produced by DCs induce CD4 T cells to undergo differentiation to Th1 cells whereas IL-10 produced by DCs induce CD4 T cells to undergo differentiation to Th2 cells. Th1 cells produce interferon-gamma (IFN- ), which enhances cellular immunity important for the clearance of intracellular pathogens and bacterial infection. Th2 cells produce IL-4, IL-5, and IL-13, which enhance humoral immunity and are important for antibody production. IL-23 causes CD4 T cells to differentiate into the Th17 subset of cells. Th17 cells produce IL-17, which attracts neutrophils to the site of bacterial infection. CD8 T cells: CD8 T cells are also called cytotoxic T cells and they recognize processed antigenic peptide presented in conjunction with MHC Class I molecules on the cell surface of DCs. CD8 T cells produce antimicrobial proteins such as perforin and granulysin that kill the host cells and the intracellular virus. CD8 T cells also produce granzymes that can induce apoptosis of host cells leading to the death of the intracellular viral or bacterial pathogens. FasL: Additionally, CD8 T cells express FasL. A variety of cells including macrophages express Fas. Binding of FasL on the cell surface of CD8 T cells with the corresponding ligand FasL on the target cells will induce apoptosis of target cells leading to the death of the target cells and the intracellular pathogen. DCs are of four types. LCs, dermal DCs, plasmacytoid DCs (PDCs) and infiltrating inflammatory dendritic epidermal cells (IDECs). LCs are the most critical and effective DCs that have the capacity to process and present foreign antigens to T cells. These resident cells are located in the epidermal layer of skin. Both IDEC and PDCs express even more costimulatory molecules, such as CD80 and CD86, than regular LC. Of note, PDCs produce large amounts of IFN- and IFN- that protect against viral infections. 3  Dermal system-Dr. Vishy Venketaraman Mast cells: Mast cells are responsible for allergies. Both answers are, of course, correct, owed to the ability of MCs to release histamine in response to allergen-mediated cross- linking of specific IgE bound to Fc RI expressed on their surface, which makes it, indeed, the most important cellular player in the induction of allergic symptoms. But there is more to it. Recent evidence from work on skin MCs suggests that their role in allergic reactions may be far more complex and that they are critically involved in the defense against pathogens invading the skin. The cells that participate in innate defenses include neutrophils, macrophages, and dendritic cells. Slide#26 Hypersensitivity reactions: The main function of the immune system is to protect the body from invading micro-organisms. Hypersensitivity is a condition where the immune system is hyperactive and damages the host cells. Hypersensitivity reactions can be classified in into three types: Type I hypersensitivity reaction: this reaction is rapid and occurs within minutes to hours. This includes allergic reactions. Type I hypersensitivity reaction is characterized by the involvement of IgE Type II hypersensitivity reaction: Type II hypersensitivity reaction is due to antibodies binding to particulate antigens resulting in complement activation and damage to the host cells. Type III hypersensitivity reaction: This is due to complement activation induced by soluble antigen-antibody complexes that can be found in the circulation. Type IV hypersensitivity reaction: This is also called delayed type hypersensitivity reaction. The cells that participate in the type IV reaction include macrophages and T cells. It takes 2 to 4 days. Slide#27-36 Type I hypersensitivity reaction is characterized by the involvement of mast cells and IgE. Initial exposure to allergens results in IgE production by B cells. IgE binds to Fc R1 (CD23) on mast cells. Secondary exposure to the same allergen, will result in the allergen binding to the IgE displayed on the mast cell surface and causing of IgE antibodies causing degranulation of mast cells and release of histamine and heparin. Histamines enhance vascular permeability and cause smooth muscle contractions. Example of type I hypersensitivity reactions: Hives (urticaria): Urticaria is characterized by raised, itchy, red blotches or wheals which may be pale in the center and red around the outside. This is also a common chemo drug reaction usually occurring within 36 hours of drug exposure. The lesions rarely last for more than 24 hours. However, on giving the drug again the lesions may develop within minutes. Atopic dermatitis: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, affecting 10-20% of children and 1-3% of adults in industrialized countries. AD occurs slightly more frequently in women than men by a ratio of approximately 1.5:1.3. The majority of cases, at least 60%, arise within the first year of life; the remainder appears in 2 4  Dermal system-Dr. Vishy Venketaraman peaks: age 2 to 12 years and from puberty into adulthood. The etiology of AD involves a complex interplay between environmental triggers and genetic factors, including altered innate and adaptive immune responses. Skin barrier dysfunction, which has very recently been shown to be genetically determined in a subgroup of AD patients, contributes to susceptibility to infections, hyperreactivity of distinct immune cells, and perhaps also to the manifestation of a high number of systemic allergic sensitizations, which profoundly direct the severity and course of the disease. Atopic dermatitis is a type I hypersensitivity reaction. But importantly in atopic dermatitis there is a biphasic T cell response during acute and chronic stage of the diseases. TH-2 CD4 T cell responses predominate during acute stage of atopic dermatitis whereas TH-1 CD4 T cell responses predominate during chronic stages of atopic dermatitis. This biphasic T cell response is due to the differential polarizing cytokines produced by langherhans cells. During acute stages of atopic dermatitis there is release of IL-10 from langherhans cells that induce differentiation of CD4 T cells to TH-2 lineage. TH-2 CD 4 T cells release IL-4 and IL-5 that induce antibody production by B cells. Allergen bound Ig E induce mast cell degranulation. During chronic stages of atopic dermatitis, langerhans cells release IL-12 that induces CD4 T cells to differentiate to TH1 lineage. Th-1 CD4 T cells release IFN- . T cells are able infiltrate the epidermis because of a T cell homing receptor called cutaneous lymphocyte associated antigens (CLA) that bind to the corresponding ligands (E-selectin and P-selectin) on endothelial cell surface leading to the infiltration. During acute stages of atopic dermatitis the innate immune responses are somewhat compromised due to lack of IFN- . IFN-  being a TH-1 cytokine is essential to activate cells of innate immune system to produce increased levels of antimicrobial peptides. Therefore, decreased levels of IFN-  will lead to reduced synthesis of antimicrobial peptides such as cathelicidins and dermicidins and this will lead to increased susceptibility to bacterial skin infections. During chronic stages of the disease there is increased IFN-, however there is decreased plasmacytoid DCs leading to enhanced susceptibility to viral infections. Plasmacytoid DCs produce IFN-alpha and beta (not IFN- ) that induce immunity against viral infections. Decreased number of plasmacytoid DCs will enhance the susceptibility to viral infections. Therefore, during chronic atopic dermatitis there is a greater incidence of viral infections. Slide#37-45 Type II hypersensitivity reactions: The antibodies involved in type II reactions are either IgG or IgM (and not IgE). In this reaction antibodies produced during the immune response recognize and bind to cell bound or particulate antigens (structural 5  Dermal system-Dr. Vishy Venketaraman components of cell surfaces). This antibody/antigen complex then activates complement proteins by “classical" pathway in the immune system to cause inflammation at the site. The result is creation of a defect on the cell's surface leading to breaking open of the cell and cell death. Example of type II hypersensitivity reactions: Pemphigus comprises a group of autoimmune and mucocutaneous blistering disorders that are good examples of type II hypersensitivity reactions. Its principal cause may be a group of antibodies directed against proteins present on the surface of keratinocytes that provide mechanical structure to the epidermis. Pemphigus vulgaris: Pemphigus vulgaris usually occurs in middle-aged or elderly patients and is rare in children. One variant, paraneoplastic pemphigus, occurs in older patients with malignancy (primarily lymphoreticular); outcome is poor. The disease is characterized by the presence of autoantibodies directed against intercellular adhesion molecules desmoglein-3 in the epidermis. They are Ca- dependent cadherins, involved in adhesion and cell signaling between epidermal cells. Acantholysis results from either direct inhibition of function of the desmogleins by autoantibody binding or from autoantibody-induced cell signaling that results in down- regulation of cell-cell adhesion and formation of blisters. These autoantibodies are present in both serum and skin during active disease. Any area of stratified squamous epithelium may be affected, including mucosal surfaces. Symptoms and Signs The primary lesions are flaccid bullae of various sizes, but often skin or mucosa just shears off, leaving painful erosions. Lesions typically occur first in the mouth, where they rupture and remain as chronic, often painful, erosions for variable periods before the skin is affected; dysphagia and poor oral intake are common. Lesions also may occur in the 6  Dermal system-Dr. Vishy Venketaraman upper esophagus. Cutaneous bullae typically arise from normal-appearing skin, rupture, and leave a raw area and crusting. Itching is usually absent. Open skin lesions often become infected. If large portions of the body are affected, fluid and electrolyte loss may be significant. Pemphigus foliaceus: Pemphigus foliaceus usually occurs in middle-aged patients. Foci of high incidence occur in South America, especially Brazil. The primary lesion is a flaccid bulla. However, because splitting occurs high in the epidermis, bullae are rarely seen; the blisters are so fragile that they rupture. Clinically, scaly, crusted cutaneous erosions, often on an erythematous base, can be seen. Mucosal surfaces are not usually involved. In one variant, pemphigus erythematosus, lesions occur in a photo distribution and are often similar to those of cutaneous lupus erythematosus. Diagnosis is by biopsy of a lesion and neighboring normal skin and by serum antibody titers against the cell adhesion molecule desmoglein 1 (160 kd). Because the disease is much more benign than pemphigus vulgaris, treatment is generally less aggressive. Bullous pemphigoid: In bullous pemphigoid, antibodies are directed against the basement membrane zone of the epidermis, causing separation between the epidermis and dermis. Bullous pemphigoid must be distinguished from pemphigus vulgaris. Patients should have a skin biopsy and serum antibody titers for hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2). Bullous pemphigoid must be differentiated from pemphigus vulgaris, linear IgA disease, erythema multiforme, drug-induced eruptions, benign mucous membrane pemphigoid, paraneoplastic pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita. Prognosis: Prognosis is good, and the disease usually subsides within months to years; however, the disease is potentially fatal, especially in the elderly and debilitated patients, with death being caused by infection and sepsis or the effects of the drugs. Linear IgA dermatosis: Very similar to dermatitis herpetiformis (DH), the symptoms begin with itchy and stingy sensation in the elbows and hands followed by the development of rash with watery blisters. The blisters resemble a strand of beads or a cluster of jewels. From the name, it is understood that the disorder is due to IgA. Again, linear IgA dermatosis is an autoimmune disorder. IgA antibodies are produced against the BPAg2 of the epidermis. Goodpasture's Syndrome (Anti-GBM Antibody Disease). Pathophysiology: Goodpasture's syndrome has a strong genetic pre-disposition and is a subtype of Pulmonary renal syndrome Individuals with HLA-DRw15, -DR4, and -DRB1 alleles are highly susceptible to Goodpasture’s syndrome. Goodpasture’s syndrome is caused due to circulating antibodies against glomerulus basement membrane. 7  Dermal system-Dr. Vishy Venketaraman The anti-glomerular basement membrane antibodies bind to the type IV collagen in the basement membrane of blood vessels in kidneys and heart. Circulating anti-GBM antibodies bind to basement membranes, fix complement, and trigger a cell-mediated inflammatory response, causing glomerulonephritis, pulmonary capillaritis, or both. Environmental exposures—cigarette smoking, viral URI, and hydrocarbon solvent inhalation most commonly and pneumonia less commonly—expose alveolar capillary antigens to circulating antibodies in genetically susceptible people. Hemoptysis and hematuria are the most common symptoms. Slide#46-49 Type III hypersensitivity reactions: With this type of reaction, immune complexes (antigen- antibody complexes) form in the circulation and deposit in various tissues where they may trigger the complement activation by "classical" pathway in the immune system. This is more widespread than the type II trigger. This process may occur in hours to days from the triggering substance. The type III reaction is more of a systemic disease. Examples of this allergic reaction are serum sickness, systemic lupus erythematosus, immune-complex glomerulonephitis (a disorder of the kidney). Dermatitis herpetiformis: This is a chronic autoimmune disease and to begin with individuals experience itchy and stinging sensation in both the elbows and knees followed by development of a rash with tiny blisters. DH is not caused by herpes infection, but it is caused due to IgA antibodies that are produced against tissue and epidermal transglutaminase. DH is common among people who suffer from gluten sensitive enteropathy (GSE). Gluten is a protein found in wheat, barley and other food products. Some people are allergic to gluten, and they suffer from GSE. DH occurs more commonly in people who suffer from gluten sensitive enteropathy. IgA produced bind to the epidermal transglutaminase in the skin leading to infiltration of neutrophils and macrophages resulting in inflammation and tissue destruction. Note that it is IgA and not E that causes DH. Systemic lupus erythematosus: Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common joint manifestations may include arthralgias and arthritis. Skin manifestations include malar and other skin rashes. The malar rashes are called butterfly erythema because it occurs in both the cheeks but spares nose and lips and hence gives a butterfly like appearance. Cardiopulmonary manifestations include pleuritis or pericarditis. 8  Dermal system-Dr. Vishy Venketaraman Obstetric manifestations: Obstetric manifestations include early and late fetal loss. Diagnosis requires clinical and serologic criteria (antinuclear antibodies [ANA]). Slide#50-60 Type IV Hypersensitive Reaction- This type of reaction is a delayed reaction (2-3 days) and involves activation of the T-cells of the immune system. The foreign substance is presented to the T-cells of the immune system, which recognizes them and sets off a series of reactions that eventually work to destroy the targeted cells. Contact dermatitis is another example of type IV hypersensitivity reaction. This manifestation of cell-mediated hypersensitivity occurs after sensitization with simple chemicals (e.g., nickel, formaldehyde), plant materials (e.g., poison ivy, poison oak), topically applied drugs (e.g., sulfonamides, neomycin), some cosmetics, soaps, and other substances. Neomycin in topical antibacterial ointment is a very common cause. Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis: Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis are related skin diseases caused primarily by cytotoxic T-cell attack on skin cells (keratinocytes). The most common triggers are herpes simplex virus-1, M. pneumoniae, and a variety of drugs, including sulfonamides and penicillins. The clinical manifestations of these diseases are characterized by a continuum of symptoms that differ in severity and anatomic location. Erythema multiforme minor is characterized by relatively few, localized target lesions on the skin, often involving the extremities, with minimal involvement of mucous membranes. They begin to heal in 7 days but may recur. In contrast, erythema multiforme major has more extensive lesions on the skin and involves the mucous membranes, often of the mouth and conjunctivae. Stevens-Johnson syndrome (SJS) has more extensive blistering lesions, often on the face and trunk with significant lesions on the mucous membranes. In SJS, less than 10% of the body surface is involved; in toxic epidermal necrolysis (TEN), more than 10% of the body surface is involved. TEN is a life-threatening disease, and treatment in a burn unit is recommended. To test whether or not an individual is previously infected with Mycobacterium tuberculosis, mycobacterial antigens are injected in the forearm of the skin. The antigen is presented by dendritic cells and 9  Dermal system-Dr. Vishy Venketaraman macrophages to memory T cells. Memory T cells (mostly CD4 T cells) proliferate and release cytokines that cause induration. If there is an induration (usually observed after 72h) of 10 mm or more, then it means that the individual is previously infected with Mycobacterium tuberculosis. Slide #61-64. Systemic Sclerosis or Scleroderma: Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis, degenerative changes, and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus, lower GI tract, lung, heart, and kidney). Common symptoms include Raynaud's syndrome, polyarthralgia, dysphagia, heartburn, and swelling and eventually skin tightening and contractures of the fingers. Lung, heart, and kidney involvement account for most deaths. Treatment is difficult, and emphasis is often on treatment of complications. Systemic sclerosis (SSc) is about 4 times more common among women than men. It is most common in the 3rd to 5th decades of life and is rare in children. SSc can develop as part of mixed connective tissue disease. Etiology: Immunologic mechanisms and heredity (certain HLA subtypes) play a role in etiology. SSc-like syndromes can result from exposure to vinyl chloride, bleomycin, epoxy and aromatic hydrocarbons, contaminated rapeseed oil, or l-tryptophan. Pathophysiology: Pathophysiology involves vascular damage and activation of fibroblasts; collagen and other extracellular proteins in various tissues are overproduced. Symptoms and Signs: The most common initial symptoms and signs are Raynaud's syndrome and insidious swelling of the distal extremities with gradual thickening of the skin of the fingers. Polyarthralgia is also prominent. GI disturbances (eg, heartburn, dysphagia) or respiratory complaints (eg, dyspnea) are occasionally the first manifestations. Skin and nail manifestations: Swelling of the skin is usually symmetric and progresses to induration. It may be confined to the fingers (sclerodactyly) and hands, or it may affect most or all of the body. The skin eventually becomes taut, shiny, and hypopigmented or hyperpigmented (Raynaud’s phenomenon); the face becomes masklike; and telangiectases may appear on the fingers, chest, face, lips, and tongue. Subcutaneous calcifications may develop, usually on the fingertips (pulps) and over bony eminences. Trophic ulcers are common, especially on the fingertips, overlying the finger joints, or over calcinotic nodules. Abnormal capillary and microvascular loops in the nails can be seen with an ophthalmoscope or dissecting microscope. Joint manifestations: Polyarthralgias or mild arthritis can be prominent. Flexion contractures may develop in the fingers, wrists, and elbows. 10  Dermal system-Dr. Vishy Venketaraman GI manifestations: Esophageal dysfunction is the most frequent visceral disturbance and occurs in most patients. Dysphagia (usually retrosternal) usually develops first. Acid reflux can cause heartburn and stricture. Barrett's esophagus occurs in 33% of patients and predisposes to complications (eg, stricture, adenocarcinoma). Hypomotility of the small bowel causes anaerobic bacterial overgrowth that can lead to malabsorption. Air may penetrate the damaged bowel wall and be visible on x-rays (pneumatosis intestinalis). Leakage of bowel contents into the peritoneal cavity can cause peritonitis. Distinctive wide-mouthed diverticula can develop in the colon. Biliary cirrhosis may develop in patients with CREST syndrome. Cardiopulmonary manifestations: Lung involvement generally progresses indolently, with substantial individual variability, but is a common cause of death. Lung fibrosis can impair gas exchange, leading to exertional dyspnea and restrictive disease with eventual respiratory failure. Acute alveolitis (potentially responsive to therapy) can develop. Esophageal dysfunction can lead to aspiration pneumonia. Pulmonary hypertension may develop, as can heart failure, both of which are poor prognostic findings. Pericarditis with effusion or pleurisy can occur. Cardiac arrhythmias are common. Renal manifestations: Severe, often sudden renal disease (renal crisis) may occur, most commonly in the first 4 to 5 yr and in patients with diffuse scleroderma. It is usually heralded by sudden, severe hypertension. Diagnosis: Clinical evaluation: Usually SCL-70 (topoisomerase I), and anticentromere antibodies. SSc should be considered in patients with Raynaud's syndrome, typical musculoskeletal or skin manifestations, or unexplained dysphagia, malabsorption, pulmonary fibrosis, pulmonary hypertension, cardiomyopathies, or conduction disturbances. Diagnosis can be obvious in patients with combinations of classic manifestations, such as Raynaud's syndrome, dysphagia, and tight skin. However, in some patients, the diagnosis cannot be made clinically. Slide#65-75 Psoriasis: Psoriasis is one of the most frequent autoimmune inflammatory skin disorders in Caucasians. It is a genetically determined disease that affects the skin, scalp and nails. It is characterized by sharply demarcated erythematous plaques with silvery scales, which appear typically on the knees, elbows, sacral region and scalp, but the entire skin may be involved. Nail changes include distal onycholysis, pitting and "oil spots". Histological characteristics of psoriasis are hyperkeratosis (thickening of epidermis), parakeratosis, acanthosis of the epidermis, tortuous and dilated capillary vessels and an inflammatory infiltrate composed mainly of lymphocytes and is located in the upper dermis. Such pathology reflects the 11  Dermal system-Dr. Vishy Venketaraman abnormal epidermal proliferation and differentiation as well as the deviated activation of the immune system. Psoriatic arthritis occurs in 5-30% of patients with cutaneous psoriasis and can appear in 10-15% of patients before involvement of the skin. It can be manifested as mono- and asymmetrical oligoarthritis, arthritis of the distal interphalangeal joints, rheumatoid arthritis- like changes, arthritis mutilans, and/or spondylitis and sacroileitis. Genetics: PSORS1 and PSORS2 genes are linked to psoriasis. Immune response to Psoriasis: Several observations suggest that psoriasis is a T lymphocyte- mediated autoimmune disease. T-lymphocytes already predominate in the cell infiltrate in psoriatic plaques in early lesions. T-lymphocytes, both CD4+ and CD8+ cells, are activated (HLA DR+ and CD 25+). In the dermis, the CD4+ cells predominate, while CD8+ cells prevail in the epidermis. One of the earliest events in the psoriatic plaques is the influx of activated CD4+ cells. In resolving plaques an influx of CD8+ cells predominate, while there is a decrease of CD4+ cells. CD4+ cells interact with APCs, expressing MHC class II antigens, while CD8+ cells interact with APCs, expressing MHC class I antigens. The induction of T-cell activation by psoriatic epidermal cells is highly dependent on the population of CD1a-DR+ dendritic cells, while CD1a+ Langerhans cells, HLA-DR+ keratinocytes and dermal dendrocytes might also be relevant APCs in psoriasis. Activated T- lymphocytes produce two different patterns of cytokines: Th1 and Th17 cells produce IL-2 and IFN- , and IL-17, respectively. Whereas Th2 cells produce IL-4, IL-5, and IL-10. Psoriasis can be considered as Th1 and Th17 dominant disease. Activated T-cells in the psoriatic plaques and other blood derived cells have been shown to secrete a series of cytokines which may account for many characteristics of the psoriatic lesion. TNF-, IL-17, IL-6, GM-CSF and IFN-  are responsible for epidermal proliferation, TNF- has been linked to the production of skin-associated antileukoproteinase and  -defensins by epidermal cells, and to IL-8 for neutrophil accumulation. On the other hand, IL-10, which is secreted by Th2 lymphocytes has been shown to inhibit the production of Th1 cytokines. The interaction between integrins of blood derived cells and ICAM-1/VCAM-1 on endothelial cells of vessels in psoriatic plaques promotes cell migration to psoriatic plaques and is crucial in the pathogenesis of psoriasis. Possible causes for Psoriasis: a) Super-antigens: Super antigens activate T-lymphocytes in a nonspecific way (MHC complex on one hand and with a variable region of the -chain of the T-lymphocyte on the other hand) and induce the expression of cutaneous lymphocyte-antigen (CLA) on T- lymphocytes. CLA binds E-selectin proteins on the endothelial cells resulting in a preferential homing of T-lymphocytes into the skin. b) Sustained T cell stimulation: In the process of activation three sets of signals between Langerhans cells and T cells take place: primary signals (e.g. TCR to MHC I or to MHC II), accessory signals (co-stimulation) and proliferation and differentiation signals. Co- stimulatory pathways between APC and the T-lymphocyte are required for full T- lymphocyte activation. One of these pathways is LFA-3 on the APC and CD2 on the surface of the T cell resulting in T-lymphocyte activation. Another co stimulatory pathway is between CD80 and CD86 (B7 molecule) on the APC and CD28 or CTLA4 on the T-cell. CD28 transmits activation and CTLA4 inhibits T-lymphocyte activity. It is also believed 12  Dermal system-Dr. Vishy Venketaraman that in psoriasis there is no CTL4 inhibition pathway leading to continued activation of T cells and pathogenesis. c) Streptococcal infection: It is also believed that infection with streptococcus can trigger T cell activation and expression of cutaneous adhesion molecules resulting in T cell migration to skin. IL-17 levels were found to be six-times higher in the skin of patients with psoriasis and treatment with secukinumab (consentyx) induces early clinical, histological and molecular resolution of psoriasis. Slide#76-88 Study Guide for Dermal Immunology lecture by Dr. Vishy Venketaraman: Structure of skin and role of skin in innate defenses (sebaceous glands, lysozyme, dermicidins and cathelicidins) Layers of epidermis (Stratum corneum, Stratum granulosum, Stratum spinosum, Stratum basale) Cells in the epidermis (keratinocytes and Langerhans), desmosomes, desmoglein-3 and 1, hemidesmosomes, bullous pemphigoid antigen-1, bullous pemphigoid antigen-2, filaggrin Cells in the dermis (dermal dendritic cells and mast cells) Types of dendritic cells (inflammatory DCs, Langerhans cells, dermal DCs and plasmacytoid DCs) Molecules on T cells (CD4, CD8, CD28, LFA and CTLA) Molecules on DCs and antigen presenting cells (MHC Class I, MHC Class II, CD80 [B7.1], CD86 [B7.2] and ICAM) Polarizing cytokines (IL-12, IL-4) Th-1 cytokines (IL-2 and IFN-) Th-1 cytokines (IL-4 and IL-5) Type 1interferons (IFN- and IFN-) Type 2 interferons (IFN-) Hypersensitivity reactions in the skin: Atopic dermatitis (biphasic CD4 T cell responses during acute and chronic stages of the disease) and Urticaria (type I hypersensitivity reaction) Type II hypersensitivity reactions (Goodpasture’s syndrome [autoantibodies against glomerular basement protein], Pemphigus vulgaris [autoantibodies against desmoglein-3, acantholysis, blisters on the skin and mucosal surface], Pemphigus foliaceus (autoantibodies against desmoglein-1), Bullous pemphigoid disease (IgG class autoantibodies against bullous pemphigoid antigen-1 and bullous pemphigoid antigen-2) and Linear IgA dermatosis (IgA class autoantibodies against bullous pemphigoid antigen-2) Type III hypersensitivity reactions: Dermatitis herpetiformis (IgA class autoantibodies against tissue and epidermal transglutaminase) and Systemic lupus erythematosus (Malar rash, anti-nuclear antibodies) Type IV hypersensitivity reactions: Tuberculin skin test, Contact dermatitis, Erythema multiforme-minor (lesions on the extremities), Erythema 13  Dermal system-Dr. Vishy Venketaraman multiforme-major (wide-spread lesions on the skin and mucous membrane), Steven-Johnson syndrome (wide-spread blistering lesions on the skin and mucous membrane on less than 10% of the body surface area), Toxic epidermal necrolysis (wide-spread blistering lesions on the skin and mucous membrane exceeding 10% of the body surface area) Autoimmune skin disorders: Scleroderma (diffuse fibrosis, Raynaud’s phenomenon, anti- topoisomerase) Psoriasis (keratinocyte proliferation leading to thickening of epidermis and scaling, superantigens, sustained T cell activation) Copyright Notice Copies of documents used in this course were made available under Section 107 of the Copyright Act of 1976, the Fair Use Statute. This material has been made available solely for use in this class and the material may not be further distributed to any person outside the class, whether by copying or by transmission in electronic or paper form. 14