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Dendritic cells

dendritic cells are part of innate immune system, antigen presenting cells in skin, activation of t cells and inducing and maintaining immune tolerance, 4 types- langerhans cells, dermal dendritic cells, merkel cells, melanocytes

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Dendritic cells

  1. 1. JAI KUMAR PILLAI KIMS, BANGALORE DENDRITIC CELLS 1
  2. 2.  Innate immunity-Immune mechanisms that are used by the host to immediately defend itself  Comprises of bariers, complements, antimicrobial peptides, cytokines, macrophages, DCs , NK cells, PMNs  Dendritic cells (DCs) are component of innate immune system. Their main function is to process antigen material and present it on the surface to T- cells, thus functioning as antigen-presenting cells. 2
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  4. 4. Location  Dendritic cells -skin ( Langerhans cells,dermal dendritic cells)  inner lining of the nose, lungs, stomach and intestines.  They can also be found in an immature state in the blood. 4
  5. 5. FUNCTIONS OF DENDRITIC CELLS  Antigen presentation and activation of T cells.  Inducing and maintaining immune tolerance.  Maintain immune memory in tandem with B cells. 5
  6. 6. TYPES OF DENDRITIC CELLS  Langerhans cells  Dermal dendritic cells  Melanocytes  Merkel cells 6
  7. 7. LANGERHANS CELLS  First described by Paul langerhans in 1868  They are bone marrow derived , dendritic ,antigen presenting cells situated in middle of epidermis  They are present in epidermis,dermis,thymus,tonsils,lymph nodes, epithelia of oral and genital mucous membranes. 7
  8. 8. Embryology  They appear by fourteenth week of fetal life  Derived from mesenchymal precursors in bone marrow • until the 12th wk, cd1a- & lack birbecks granules not present 8
  9. 9.  They are distributed in basal ,spinous and granular cell layers,  They constitute 2% to 8% of total epidermal cell population.  They vary in distribution according to their anatomical sites, their number ranging between 460 and 1000/sqmm of epidermis. 9
  10. 10.  Within the epidermis LCs are anchored to surrounding keratinocytes by E-cadherin mediated homotypic adhesions  Dermal CD14/Cd11c have the potential to differentiate into LCs under TGF-B1 10
  11. 11.  Plasmacytoid dendritic cells- In conditions SLE, virus infectn, psoriasis, allergic CD. Non-indigenous DCs precursors characterized by highly dev ER(plasma cell like appearance) enters the skin  Produce natural IFNs in respone to TLR ligand  Hence named principal type IFN producing cells 11
  12. 12.  In conditions like Atopic dermatitis, contact eczema another non indigenous DC precursors originate from myeloid precursors  Inflammatory dendritic epidermal cells  Characterized by expression of CD1a, CD1b, CD23 & CD36  Immune response triggered by these is in TH112
  13. 13. Danger signals TLR ligands, chemical haptens, hypoxia  LCs enlarges,downregulation of Fc receptors & E- cadherin, increased MHC 2  Migrate downward into dermis-enter afferent lymphatics- reach T cell zones of lymph node  TNF-a & IL-1B stimulates this process  To penetrate BM, LCs attach to it via a6 containing integrin receptors producing type 4 collagenase(MMP9)  Osteopontin 13
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  15. 15. Histology  Light microscopy : pale staining & convoluted nuclei 15
  16. 16. On EM: lobulated nucleus • Absence of tonofilaments, desmosomes • Flat plate like structure with hemispherical blebs at one end (birbecks granule) • C/S app: tennis racquet shape. `  arise from infolding of plasma membrane function as phagosomes that digest extracellular material 16
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  18. 18.  Identified by special techniques like impregnation by gold chloride ,staining by ATPase and alpha-D-mannose. Immunohistochemical Markers  ATPase +ve , DOPA negative  S100, CD1a +ve  HLA-DR,DP,DQ antigen +ve  Recently identified Langerin(CD207)-single best marker 18
  19. 19. Other importance  Membrane receptors for C3b & Fc portion of IgG  Recognition of antigens& cell mediated immunologic reactions as allergic CD  Allograft rejection(1a antigens)  Immune surveillance against UV neoplasia(UV decreases no. of langerhans cells) 19
  20. 20. FUNCTIONS  cutaneous immune mechanism,especially in antigen presentation ,  stimulation of T cell response  phagocytosis  regulation of epidermal differentiation 20
  21. 21. APPLIED ASPECTS Implicated in various immune processes  allergic contact dermatitis,  HIV,  allograft rejection,  immune tolerance and  surveillance against neoplasia.  Psoriasis, sarcoidosis, CD their no. in skin is reduced  Because of their antigen presenting ability they have become prospective vehicle for tumor therapy and tumor vaccines 21
  22. 22. Dermal Dendritic Cells  Bone marrow derived leukocytes having migratory and AP property  Markers include CD1b, CD1c, subunitA of clotting factor X111  Differentiated from macrophages • expression of MHC 2 • CD205 • absence of phagolysosome  DDC are located in the vicinity of superficial plexus  DDC proliferate constitutively in human dermis 22
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  24. 24. MELANOCYTES  Dendritic cells that synthesize and secrete melanin contaning organelles called melanosomes.  Appearance of melanocytes in epidermis takes place in craniocaudal direction  in accordance with the development of neural crest from which they are derived. 24
  25. 25. EMBRYOLOGY  Neural crest, they migrate to epidermis, various mucous epithelia, hair follicle, dermis, leptomeninges inner ear, uveal tissue  In retina originate from optic cup of primitive forebrain  Primitive melanocytes in skin are first found during eighth week of fetal life  At 5mon melanosomes begin to transfer pigment to keratinocytes 25
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  27. 27. `  They express integrin receptors and use them to migrate to epidermis during development  Melanoblast migration and differentiation into melanocytes • Wnt , ET3, BMPs • Steel factor, c-kit , HGF 27
  28. 28. MITF affects melanoblast differentiation by inducing tyrosinase, TRP1& dopachrome tautomerase(TRP2) 28
  29. 29.  BMPs- disulfide linked dimeric proteins  belongs to TGF-B family  Signaling suppresses neural crest differentiation into melanoblast  Functions as Wnt antagonists 29
  30. 30.  Endothelins bind & activate transmembrane G protein linked receptors EdnrA , B  Ednr B receptors imp for melanoblast migration and proliferation  Defect causes waardenburg synd & Hirschsprung synd 30
  31. 31.  SF-early melanoblast development requires cytokine SF and its TK transmembrane receptor c-kit Mutn of c-kit/Sf causes Piebaldism  HGF is ligand for transmembrane TK receptor met, also essential for melanoblast proliferation & differentiation 31
  32. 32. Types  Dendritic :- these are capable of pigment transfer to other cells  Non-dendritic :- they retain the melanosomes synthesized Eg: uvea, retina , leptomeninges 32
  33. 33. Site specific melanocytes 1]Cutaneous Melanocytes • Largest no. of melanocytes • Skin & hair follicle • Part of “epidermal melanin unit” 2] Melanocyte stem cells • present in hair follicle bulge • Express TRP2 & nestin • Other transcription factr- SOX10 & Pax5 33
  34. 34. 3]Ocular melanocyte uveal tract; they do not transfer their melanosomes required for proper routing of I/L & C/L neural fibres in optic chiasm Imp: visual abn in pts with albinism 34
  35. 35.  4]Otic Melannocyte • reside in cochlea & imp for hearing • Maintainence of endolymph through regulation of K transport • Imp: Waardenburg synd  5]CEPHALIC Melanocyte distributed through out the meninges & more dense in leptomeninges above pons & medulla oblongata. 35
  36. 36. Epidermal melanin unit  Assn between dendritic melanocytes and keratinocytes within epidermis  One melanocyte is in contact with 36 basal and suprabasal keratinocyte  Ratio of melanocyte to keratinocyte in basal layer of epidermis varies frm 1:4 to 1:10 36
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  38. 38. DISTRIBUTION  Melanocytes are more abundant in skin of face and male genitalia upto 2900/mm2 than on trunk upto 1250/mm2  As a rule greater amount of melanin is present in basal keratinocytes than in melanocytes  basal cells at tip of rete ridges are more38
  39. 39. MELANIN SYNTHESIS AND MELANOSOMES  Melanin is produced in melanosomes(pigment granules or organelles)  A key protein involved in melanosome assembly is NCKX5 encoded by SLC24A5.  The major hormone controlling melanin synthesis is MSH from the pitutary gland. 39
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  41. 41. Melanin Synthesis  Synthesis of melanin starts with the conversion tyrosine to dihydroxyphenyalanine(dopa) by tyrosinase, a copper containing, aerobic enzyme  Critical, rate limitting step {Raper-mason pathway}  Then dopa is oxidized to dopaquinone by tyrosinase 41
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  43. 43.  These reactions occurs in melanosomes  then passed on to surrounding keratinocytes  undergo series of developmental and biochemical stages; STAGES OF MELANIZATION  Stage1:melanosomes are spherical, membrane bound vesicles 0.3um composed of longitudinally oriented concentric lamellae. No melanin. 43
  44. 44.  Stage2: melanosomes are ellipsoidal 0.5um Melanin deposited within cross-linked long filaments .  Stage 3: melanin deposition increases by enzymatic and non-enzymatic polymerizatn  Stage 4: melanosomes are fully developed and electron opaque because of dense deposits of melanin. mainly by polymerization 44
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  47. 47.  Between these electron dense melanized cores and their outer membranes mature melanosomes house distinct vesicles 40nm in diameter called vesiculoglobular bodies.  Inv in internal organization & melanization of eu- and pheomelanosomes  During progression from stage 1 to stage 4 tyrosinase decreases and acid phosphatase increases( helping in degradation) 47
  48. 48. FACTORS INFLUENCING MELANIN SYNTHESIS  UV LIGHT : Increases melanocytes  HORMONES:MSH,ACTH, oestrogen, progestrone,Androgens,lipotropins,thyroxine all have melanocyte stimulating property  OTHERS:- pgd2,pge2,arachidonic acid,oleic acid  AGEING : Causes decrease in follicular melanocytes 48
  49. 49. TYPES OF MELANIN  Eumelanin • insoluble • produced in eumelanosomes • Large,elliptical • Highly structured fibrillar glycoprotein matrix • black and brown colour of skin and hair  Pheomelanin • Sulfur containing, soluble • Pheomelanosomes • Smaller, spherical • Disorganised and loose glycoprotein matrix • lighter colour of hair 49
  50. 50. Melanosome transport  Once melanosomes are formed, melanized and reach tips of dendrites,  they are transported from melanocytes to keratinocytes by apocopation  Keratinocytes phagocytize the melanosome laden tips of melanocytic dendrites  In the epidermis melanosomes become concentrated in a umbrella like array above nuclei of keratinocytes on the side towards skin surface i.e. on the sunny side of nuclei 50
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  52. 52.  Following transfer to keratinocytes  fully melanized melanosomes are conveyed upwards as basal keratinoctes mature  are eventually degraded by lysosomal enzymes and  shed as cornified cells are desquamated. 52
  53. 53. COLOUR OF SKIN  Absolute number of melanocytes in human skin is same for both sexes and all races.  Differences in color among the races result from differences in the 1.number 2.size 3.degree of melanization 4.distribution 5.rate of degradation of melanosomes within keratinocytes 53
  54. 54. NORMAL MICROANATOMY  On staining with H&E they contain round to oval dark stained nuclei and clear halo of surrounding cytoplasm 54
  55. 55.  On electron microscopy,these cells characteristically ‘hang down’ from basal cell layer and are devoid of tonofilaments or desmosomes.  abundant melanosomes in varying stages of melanisation.  numerous mitochondria , well developed RER Golgi55
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  57. 57.  Melanin can be bleached by strong oxidizing agent such as H2O2 or KMNO4 DOPA reaction- unfixed tissue of enzymatically seperated epidermal sheets are incubated in 0.01% soln of 3-4 dihydroxyphenylalanine this stains functional active melanocyte as dark brown or black. 57
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  59. 59. IMMUNOHISTOCHEMICAL TECHNIQUE ANTIGEN ANTIBODY POSITIVE CELLS ANTIGEN LOCATION S100 PROTEIN Anti-S100 PROTEIN Melanocytes,lan gerhans cells,schwann cells,adipocytes, myoepithelial cells of sweat glands Nuclear and cytoplasmic gp100 HMB-45 Fetal melanocytes,acti vate adult melanocytes Cytoplasmic Melan-A/MART-1 A103/M2-7C10 Melanocyte Cytolplasmic Tyrosinase T311 Melanocytes Cytoplasmic PNL2 ANTIGEN PNL2 ANTIBODY Melanocytes Cytoplasmis 59
  60. 60. FUNCTIONS OF MELANIN  Absorption of UV (phototoxic and photosensitize)  Thermoregulation  Free radical quencher  Protection against lipid peroxidation  Photoprotection, photoageing  Protection from photocarcinogenesis,  Regulation of vit D synthesis.  Camouflage and sexual appeal. 60
  61. 61. APPLIED ASPECTS  In vitiligo melanocytes are destroyed.  In albinism melanocytes are normal in number but unable to synthesize fully pigmented melanosomes because of defective enzymatic formation of melanin.  Freckles result from increase in production of pigment by normal number of melanocytes.  Nevi are benign proliferations of melanocytes  Malignant counterpart - melanoma 61
  62. 62. MERKEL CELLS  In 1875,FRIEDRICH MERKEL identified at base of rete ridges cells that were in contact with nerve fibrils and named them tastzellen or touch cells.  Slow adapting type1 mechanoreceptors in sites of high tactile sensitivity 62
  63. 63. Embryology  Appear in fetal skin by sixteenth week of gestation.  They originate in the epidermis itself, presumably from germinative keratocytes 63
  64. 64.  Found in basal layer of epidermis  In hairy skin & glabrous skin of digits, lips, regions of oral cavity , outer root sheath of hair follicle  They are arranged in groups at tips of rete ridges. 64
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  66. 66. STRUCTURE  Electron lucent cytoplasm rich in organelles  Lobulated nuclei  Margins of cells project cytoplasmic “spines” towards keratinocytes  Poorly developed desmosomes,delicate cytoplasmic microfilaments.  Characteristic spherical granules which are membrane limited with a dense central core 66
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  68. 68.  Merkel cells are supplied by myelinated nerves  as they near epidermis lose their myelin sheaths and continue as unmelinated axons  surrounded by cytoplasm and basement membranes of schwann cells.  The nerve fibres terminate in flat,meniscus like contacts that are studded along basal aspects of merkel cells. 68
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  70. 70.  On silver impregnated sections, the meniscoid nerve terminal that covers basal portion of each merkel cell can be seen as merkel disk.  Immunohistochemical markers :-  K8, K18, K19 & K20  K20 is highly specific for merkel cells. 70
  71. 71.  Merkel cells express neuroendocrine markers such as chromogranin A and synaptophysin.  Neurosecretory substances in particular neuropeptides that are stored in densecore granules include VIP , CGRP, Serotonin, substanceP. 71
  72. 72. FUNCTIONS  They are slowly adapting , low threshold type 1 mechanoreceptors.  They may enhance or induce the excitability of sensory nerve endings via release of neuropeptides. 72
  73. 73. APPLIED ASPECTS  Merkel cell hyperplasia with keratinocyte hyperproliferation is seen in adnexal tumors such as naevus sebaceus, tricoblastomas, trichoepitheliomas, nodular hidradenomas.  Merkel cell hyperplasia with hyperplasia of nerve endings neurofibromas neurilemmomas, nodular prurigo neurodermatitis 73
  74. 74. THANK YOU 74

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