• Information
  1. Immunologic Cells of the Skin
  2. Keratinocytes
  3. Langerhans Cell
  4. Cutaneous T Lymphocytes
  5. Limited Classification of Diseases
  6. Atopic Dermatitis
  7. Urticaria
  8. Allergic Contact Dermatitis
  9. Autoimmune Bullous Diseases
  10. Langerhans' Cell Histiocytosis
  11. Dermatomyositis
  12. Systemic Lupus Erythematosus
  13. Scleroderma

A. Immunologic Cells of the Skin

1. Keratinocytes
2. Langerhans' Cells
3. CLA+ T lymphocytes
4. Thy-1+ dendritic cells (murine only)

B. Keratinocytes

1. Innate Immune System [9]
   1. Keratinocytes produce specific antimicrobial peptides
   2. Innate immune system of skin contains antimicrobial peptides
   3. These include cathelicidins (such as LL-37) and ß-defensins (such as HBD-2)
2. Class II Expression and Tolerance Induction
   1. Keratinocytes can be actived aby cytokines to express Class II MHC
   2. Normally do not secrete or express T-cell costimulatory signals
   3. Therefore, appear to play a role in tolerance induction
   4. T cells activated by Class II without costimulation are tolerized (anergic)
   5. Keratinocytes do store preformed IL1a which can be released on infection or inflammation
3. Cytokine Activation
   1. Th1 lymphocyte infiltration is primary stimulus to keratinocytes
   2. Keratinocytes express ICAM-1 induced by IFN gamma (IFNg) and TNF alpha (TNFa)
   3. IFNg and TNFa stimulate binding of lymphocytes to skin
4. Cytokine Inhibition [9]
   1. Th2 cytokines (IL4, IL5, IL13) stimulate eosinophil and plasma cell recruitment to skin
   2. Also stimulate IgE production and mast cell infiltration
   3. Th2 cytokines inhibit expression of innate antimicrobial peptides
   4. This can lead to increased colonization and superinfection by bacteria
5. May play a role in autoimmunity

C. Langerhans Cell (LC)

1. Bone marrow derived (mesenchymal) cell found in epidermis
2. Dendritic shaped cells, supra basal location
   1. EM identifies characteristic granules, Birbeck granules
   2. These tennis racquet shaped granules have unknown function
   3. Dermal dendritic cells are also found with similar function
3. Comprise ~3-4% of epidermal cells
4. Surface expression
   1. Class II MHC: HLA-DR, DP, DQ
   2. CD1, CD4
   3. Fc-GR and C3-R
   4. LFA-3 and ICAM-1
5. Primary function is Antigen Presentation
   1. Expression of MHC Class II (an stimulate mixed lymphocyte reaction)
   2. Expression of LFA-3 and ICAM-1 accessory binding molecules
   3. Secretion of IL1 (T cell accessory factor) costimulator for T lymphocytes
   4. Ability to process antigen (proteolytic degradation) for presentation on MHC
6. LC also have role in initiating skin graft rejection
   1. First stimulate helper T lymphocytes (CD4+)
   2. These cells help cytotoxic T cells (CD8+) reject skin graft
7. UV exposure results in altered LC and decreased ability to present antigen

D. Cutaneous T Lymphocytes [1,8]

1. Primary function appears to be cutaneous immune surveillance
2. Also play a role in autoimmunity and neoplasia
3. Subpopulation of T cells that are retained in skin
   1. Express several cell adhesion molecules (CAMs) which facilitate skin localization and activation
   2. Prominent marker is cutaneous lymphocyte antigen (CLA) which binds to E-selectin
   3. These cells make up 10-15% of all circulating peripheral blood T lymphocytes
   4. CLA+ T cells may express either CD4 or CD8
   5. Activated CLA+ T cells can produce Th1 or Th2 type cytokines
4. CLA+ T lymphocytes may be reatined preferentially in skin
   1. Under normal situations, majority are found in local lymph nodes
   2. Migration to in areas of high endothelium venules (HEV) through selectins and integrins
   3. CLA itself is an adhesion molecule binding E-selectin
   4. Specific homing of CLA+ T cells to skin in vivo has not been demonstrated [8]
   5. Activation of migrated T cells requires additional cytokines and cell interactions
   6. Migrated T cells interact with local dendritic (Langerhans and dermal) cells
5. Stimulation of CTL+ T lymphocytes
   1. T lymphocytes are stimulated by antigen + MHC and also require a second signal
   2. The second signal is usually initiated through cytokines or Toll-receptor pathways
   3. Epidermal keratinocytes store IL1a
   4. Keratinocytes can also produce IL1b and TNFa
   5. Bacterial products and other macromolecules can stimulate lymphocytes through Toll-like receptors
   6. Cytokine and Toll signalling stimulate nuclear factor kappa-B (NF-kB) pathways
   7. NF-kB stimulates many inflammatory genes including cytokines, selectins, other CAMs
   8. CAMs are likely required

1. Allergic
   1. Atopic Dermatitis
   2. Urticaria
2. T Cell Mediated Immune Disorders
   1. Psoriasis
   2. Allergic Contact Dermatitis (see below)
   3. Autoimmune Bullous Diseases
3. Langerhans' Cell Abnormalities
4. Rheumatologic Syndromes with Skin Involvement (see below)
   1. Systemic Lupus Erythematosus (SLE)
   2. Systemic Sclerosis (Scleroderma)
   3. Dermatomyositis
   4. Vasculitic Syndromes
5. Other
   1. Cutaneous T Cell Lymphoma (CTCL)
   2. Graft Versus Host Disease (GVHD)

B. Atopic Dermatitis [6]

1. Inflammatory skin condition with dermatitis and pruritus
2. Often occurs in patients with personal or family history of allergy and/or asthma
3. House dust mite Dermatophagoides pteronyssinus is frequently causative
4. Exaggerated cutaneous immune response to environmental antigens [9]
   1. Highly elevated levels of IgE, correlated with overproduction of IL4
   2. Probably due to preferential development of CLA+, T helper type 2 cells
   3. IL4, IL13, IL5, and IL13 are increased leading to elevated IgE levels
   4. Interferon gamma production and defensins/cathelicidins are suppressed

C. Urticaria [6]

1. Like atopic dermatitis, usually due to IgE dependent (Type 1) hypersensitivity
2. Circumscribed, raised, erythematous evanescent areas of edema
   1. Urticaria involves only the superficial portion of dermis
   2. Angioedema involves the deep dermis and/or subcutenaous layers
3. Appears suddenly; rarely persists >24 hours
4. Usually highly pruritic
5. Common Inciting Agents
   1. Foods
   2. Drugs
   3. Aeroallergens

D. Allergic Contact Dermatitis [6]

1. Classification
   1. These are all classical Type IV Hypersensitivity reactions
   2. Majority with subacute inflammation
   3. Poison ivy, sumac, oak are more acute
   4. Langerhans cells take up antigen and process for presentation
   5. In addition, Toll-receptor pathway may be utilized
   6. Endothelial adhesion molecules are expressed leading to T cell recruitment
   7. Activated CLA+, CD4+ T cells are found in lesions
   8. Repetitive exposure to sensitizing antigen leads to escalating immune responses
2. Common Causes
   1. Majority are usually unstable reactive molecules: form complexes with host proteins
   2. Poison ivy, sumac, oak
   3. Rubber
   4. Topical medications - neomycin, bacitracin, quinolines
   5. Resins - epoxy, butylphenyl-formaldehyde
   6. Various cosmetics and hair dyes
   7. Metals - nickel, cobalt, potassium dichromate
3. Poison ivy is the prototypical causative agent
   1. Erythematous, edematous papules and plaques erupt 6-24 hours after contact
   2. The patient must have been sensitized; the active agent is Urushiol
4. Treatment
   1. Removal of offending agent
   2. Topical glucocorticoids creams
   3. Antihistamines may be of some minor benefit

E. Autoimmune Bullous Diseases [4]

1. Pemphigus Vulgaris
2. Bullous Pemphigoid
3. Herpes Gestationis
4. Epidermolysis bullosa aquisita
5. Linear IgA Dermatosis
6. Bullous Erythema Multiforme

F. Langerhans' Cell Histiocytosis

1. Proliferation of Langerhans' type histiocytes (variable Birbeck granules) [7]
   1. Malignant disorder of dendritic Langerhans' Cells of skin and other organs
   2. Clonal proliferative disorder - proved by PCR of X-chromosome loci in female patients
2. Variable Clinical Syndrome
   1. Cutaneous involvement of the disease correlates with severity of illness
   2. That is, this disease has a wide spectrum of presentation and progression
   3. Can be a lethal leukemic disorder
   4. Multifocal local lesions
   5. Solitary lytic lesion of bone (eosinophilic granuloma)
3. Related Entities
   1. Letterer-Siwe Disease - true histiocytosis X
   2. Hand-Schuller-Christian Disease
4. Systemic Infiltration
   1. Hepatosplenomegaly
   2. Lymphadenopathy
   3. Cytopenias (marrow involvement)
   4. Diabetes insipidus (posterior pituitary)
   5. Exophthalmos (Cranial Nerve involvement)
   6. Pulmonary (especially in eosinophilic granuloma)
5. Cutaneous Infiltration
   1. Infiltration of dermis and epidermis by mononuclear cells with oval nuclei
   2. Eosinophilic cytoplasm with nuclear pleomorphism (kidney shaped)
   3. Epidermal necrosis is common
   4. Diagnosis confirmed by immunohistochemistry and EM on biopsy sample
6. Treatment
   1. Vincristine, Vinblastine
   2. Other chemotherapy

G. Dermatomyositis

1. Etiology
   1. Idiopathic probable autoimmune disease
   2. Mediated by CD8+ (some CD4+) T cells and Immune complexes
   3. Underlying cancer in minority of cases
   4. May lead to significant rhabdomyolysis
2. Symptoms
   1. Rash can occur nearly anywhere and may be photosensitive
   2. Eruption on upper eyelids (Heliotrope Rash)
   3. Erythematous, violaceous scale like rash on knuckles
   4. Gottren's Papules - usually on hands
   5. Periungual telangiectasia
   6. Muscle weakness is usually proximal, particularly thighs
   7. Swallowing problems occur also due to muscle involvement
   8. Pulmonary disease is common
3. Differential is very long

H. Systemic Lupus Erythematosus (SLE) [2]

1. Types of Lesions specific for SLE
   1. Acute Cutaneous LE - usually localized but may be diffuse
   2. Subacute Cutaneous LE - psoriasiform, annular polycyclic (SCLE)
   3. Chronic Cutaneous LE - discoid LE, hypertrophic or verrucous LE, palmer or plantar LE
   4. Lupus panniculitis - deep lesions, nodules, may ulcerate
2. Histology of Affected Skin
   1. Sparse, superficial infiltrate in subacute cutaneous LE with epidermal IgG
   2. Dense, deeper infiltrate in discoid LE
   3. Classic dermal-epidermal junctional staining, called "lupus band"
   4. The lupus band represents immune complex staining
   5. Thickened basement membrane
3. Other Lesions in LE
   1. Telangiectasias
   2. Rheumatoid nodules
   3. Livedo reticularis - often associated with anti-phospholipid antibodies
   4. Alopecia (often scarring)
   5. Urticaria
   6. Photosensitivity
4. SCLE [10]
   1. Cutaneous form of SLE
   2. Less systemic involvement than SLE (typically <20% of cases)
   3. Intense photosensitivity is primary
   4. Polyarthritis in ~35%; polyarthralgias common
   5. Most cases ANA+ with ~65% anti-Ro+
   6. Discoid lupus is one variant of SCLE
5. Treatment of Skin Disease in SLE
   1. ~70% of patients will respond to hydroxychloroquine (Plaquenil®)
   2. Atabrine has been found to be effective in discoid lupus when hydrochloroquine fails
   3. Dapsone, azathioprine, and other drugs have been used in resistant cutaneous LE
   4. Gold, intralesional interferon, retinoids have been used also

I. Scleroderma

1. Symptoms
   1. Localized Scleroderma - often called CREST; skin on hands mainly affectd
   2. CREST: Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly and Telangiectasia
   3. Generalized Scleroderma - lungs, kidneys, gastrointestinal tract, prominantly affected
2. Autoimmune Antibodies
   1. Anti-Centromere - associated with CREST (~75% of cases)
   2. Anti-Topoisomerase I (Scl-70) Antibodies (~20% of cases)
3. Differential Diagnosis
   1. Localized: morphea, linear scleroderma
   2. Generalized: CREST, Overlap Syndromes (particularly with lupus and myositis)

References

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2. Boumpas DT, Fessler BJ, Austin HA III, et al. 1995. Ann Intern Med. 123(1):42
3. Gallin JI, Farber JM, Holland SM, Nutman M. 1995. Ann Intern Med. 123(3):216
4. Fine JD. 1995. NEJM. 333(22):1475
5. Ruzicka T, Bieber T, Schopf, et al. 1997. NEJM. 337(12):817
6. Leung DYM, Diaz LA, DeLeo V, Soter NA. 1997. JAMA. 278(22):1914
7. Willman CL, Busque L, Griffith BB, et al. 1994. NEJM. 331(3):154
8. Westermann J, Engelhardt B, Hoffmann JC. 2001. Ann Intern Med. 135(4):279
9. Ong PY, Ohtake T, Brandt C, et al. 2002. NEJM. 347(15):1151
10. Hsu S, Le EH, Khoshevis MR. 2001. Am Fam Phys. 62(2):289