Immunology concepts applicable in dermatology.pptx

Presentation on immunological concepts in Dermatology

1. CLINICAL IMMUNOLOGY MODERATOR : DR DEVRAJ DOGRA PRESENTED BY: DR ABHINAV CHAWLA

2. ACKNOWLEDGEMENTS I would like to thank my co-PGs, seniors and faculty for giving me a chance and guiding me in creation of this presentation. My thanks are due to all authors and publishers of books and articles that have been consulted in this process.

3. INDEX SERIAL NUMBER TITLE 1. INTRODUCTION 2. INNATE IMMUNITY 3. CELLS PARTICIPATING IN IMMUNE RESPONSE 4. ADAPTIVE IMMUNE RESPONSE 5. JAK STAT PATHWAY 6. GRANULOMATOUS INFLAMMATION 7. ALLERGIC CONTACT HYPERSENSITIVITY 8. BIBLIOGRAPHY

4. SECTION 1 INTRODUCTION

5. PARAMETERS INNATE IMMUNITY ACQUIRED IMMUNITY DEFINITION Resistance to infections that is present since birth Resistance to infections that is acquired during lifetime TIME Within minutes Within days SPECIFICITY Non specific Specific MEMORY Lacks memory Memory is present DIVERSITY Limited Active against a range of infections COMPONENTS Barrier Circulating factors Cells B cells T cells Antigen producing cells

6. LOCAL IMMUNITY :- Provided by IgA. At mucosal surfaces i.e. GIT and Respiratory mucosa. Very high amounts of IgA is produced to coat entire mucosal surface…however its serum levels are lower than IgM and IgG . HERD IMMUNITY :- Refers to immunity of the whole population towards a pathogen. Good herd immunity decreases the chances of epidemics due to pathogens. Provided by mass administration of live vaccines to all susceptible individuals of a population .

7. SECTION 2 INNATE IMMUNITY

8. INNATE IMMUNITY 3 Components :- Barriers Physical Chemical Biological Circulating factors C. Cells Tissue Macrophages Dendritic cells Neutrophils Monocytes

9. A. BARRIER LOCATION MECHANICAL CHEMICAL BIOLOGICAL SKIN Keratinised Squamous epithelium 1. Fatty acids Skin flora 2. Defensins GIT 1. Mucins Gastric acid IgA 2. Peristalsis GENITOURINARY TRACT Urine flow Low pH IgA RESPIRATORY TRACT 1. Air flow Surfactant IgA 2. Ciliated lining

10. DEFENSINS :- Positively charged peptides that are produced in GIT and Lower Respiratory tract. Function :- Create pores in the lipid membranes of bacteria, fungi and some viruses. 2 types :- Alpha : Present in GIT(Paneth cells and Neutrophils); Have antiviral activity B eta : Present in Respiratory tract; Have Anti B acterial activity. SURFACTANT :- Lipoproteins produced in lung alveoli that bind to surface of microbes leading to phagocytosis.

11. CLINICAL APPLICATIONS :- CONDITIONS MECHANISM RESULTS IN BURNS Disruption of epithelial lining Increased risk of infections CYSTIC FIBROSIS Interruption of mucus and cilia Infections and severe lung disease SJOGREN SYNDROME Decreased tear, saliva and mucus production Increased risk of infections at these sites ACHLORHYDRIA Gastric atrophy/ PPI induced Decreased resistance to Candida and Enteric infections.

12. CIRCULATING FACTORS :- A. COMPLEMENT : Refers to a family of 20 proteins that augment the effects of other components of immune system. 3 main effects :- G eneration of mediators : that participate in inflammatory response. L ysis : of bacteria and tumour cells O psonisation : Enhancement of phagocytosis

13. ACTIVATION OF COMPLEMENT :- 3 pathways :- Classical Pathway Alternative Pathway Lectin pathway Antibody is not necessary to activate complement in case of alternate and lectin pathway; thus these pathways are important in case of 1 st time infection.

14. ALTERNATE PATHWAY :- Unrelated cell surface substances (LPS, Fungal cell wall, Viral envelope) Bind to C3 (C3a and C3b) and Factor B (Ba & Bb) Factor D (acts as a protease) C3bBb (Acts as C3 convertase) Generates more C3b Leading to an Amplification loop

15. Complement Deficiency disorders 1.PROPERDIN DEFICIENCY X linked disorder with susceptibility to Neisseria infections. 2. C1 inhibitor deficiency Hereditary Angioedema with low C4 and normal C1 levels. C2 deficiency C3 deficiency C4 deficiency INHERITED ACQUIRED

16. B. CYTOKINES :- “Cytokines are the language of the immune system and immune cells use cytokines to communicate with other cells” Historically, these were named after the function discovered for them, e.g. TNF alpha or G-CSF. INTERLEUKIN : Cytokines that are produced by White Blood cells and exert effects on other White Blood Cells, COLONY STIMULATING FACTOR : Mediates differentiation and proliferation of hematopoietic progenitor cells. INTERFERONS : Interfere with viral replication.

17. Early innate responses are dominated by cytokines with inflammatory and antiviral actions {e g IL 1, IL 6, IL 18, TNF alpha and IFN beta} Adaptive immune response is dependent on Immunomodulatory cytokines, which includes IL 2, 4, 12, 13, 17, 22, 23 & IFN Gamma.

18. INTERFERONS :- Glycoproteins that were originally named as these interfered with VIRAL REPLICATION. Actually, these are innate cytokines with multiple other effects on cells 2 types :- TYPE 1 Interferons TYPE 2 [Gamma Interferon] INF alpha INF Beta Interferon Gamma is produced by activated T cells and NK cells. ITS NAME IS BECAUSE OF STRUCTURAL SIMILARITY TO THE REST 2 INTERFERONS; HOWEVER ITS MAIN FUNCTION IS TO ACTIVATE MACROPHAGES.

19. IFN Alpha Produced mainly by the PLASMACYTOID DENDRITIC CELLS. Mainly involved in viral infections. Used as INTERFERON ALFA : Hairy Cell Leukemia Parkinsonism 3. Hepatitis C : Previously used in Hepatitis C along with Ribavirin IFN Beta Produced in large quantities by FIBROBLASTS. Have an antiviral activity.

20. TOLL- LIKE RECEPTORS PATTERN RECOGNITION RECEPTORS[PRRs] mediate responses to PAMPs [Pathogen associated molecular patterns] that are conserved among microbes. TOLL-LIKE RECEPTORS are the human analogues of Toll receptors found in Drosophila and are one such family of PRR. 10 TLRs have been identified to date and labelled as TLR 1 to 10. SERIAL NO. TLR RECOGNITION OF 1 TLR 1,2,6 LIPOPROTEINS & PEPTIDOGLYCANS 2 TLR 4 LIPOPOLYSACCHARIDES 3 TLR 5 FLAGELLIN 4 TLR 9 BACTERIAL CpG SEQUENCES

21. SERIAL NO. TLR RECOGNITION OF 5 TLR 3 Viral dsRNA 6 TLR 7 Viral ssRNA 7 TLR 8 Viral ssRNA 8 TLR 10 Unknown

22. Activation of TLRs by microbial components Maturation & Migration of dendritic cells in LN, where these present pathogen derived Ag to T cells Different TLRs induce T cells differently, and thus, different subtypes of T cells are produced in response to the TLR

23. INFLAMMASOME Complexes of innate immune system components that sense PAMPs. 4 types have been identified :- SERIAL NO. INFLAMMASOME ACTIVATED BY 1 Aim2 dsDNA {viral/ bacterial origin} 2 NLRP1 Muramyl peptides 3 NLRP3 Multiple PAMPs {CONSIDERED MOST IMPORTANT INFLAMMASOME} 4 NLRC4 Flagellin

24. RESULT OF INFLAMMASOME ACTIVATION :- Pro IL 1beta gets converted to IL 1beta which is a highly potent inflammatory mediator. Dysregulation of inflammasomes leads to CAPS [Cryopyrin associated Periodic Syndromes] that are associated with recurrent episodes of fever, urticarial lesions, arthritis and systemic inflammation. These respond well to IL 1 blockers

25. CHEMOKINES :- This term is a combination of Chemo tactic and cyto kine. DEFINITION :- Family of small cytokines or signalling proteins secreted by cells that induce directional movement of leukocytes. Signal through GPCRs.

26. These are small polypeptides that are classified on basis of structure :- A few other chemokines have unusual structures, including :- Lymphotoxins :- C chemokines Fractalkine :- Only CX3C cytokine. PARAMETERS ALPHA CHEMOKINES BETA CHEMOKINES CHEMISTRY Cys -X- Cys Cys-Cys ATTRACTS Neutrophils Monocytes PRODUCED BY Activated mononuclear cells Activated T cells EXAMPLES IL-8, Eotaxins RANTES, CCL2

27. There are specific receptors on cells for chemokines. Interaction of the chemokine with its receptor causes cell to adhere to and migrate between the endothelial cells to the site of infection.

28. SECTION 3 CELLS PARTICIPATING IN IMMUNE RESPONSE

29. MACROPHAGES & NEUTROPHILS :- Derived from monocytes, and have special carbohydrate receptors ( e g mannose) that are not usually present on vertebrate cells , so as to distinguish “self” cells from “non self” cells. Also have receptors for antibodies and complement. After phagocytosis, microbes are exposed to multiple toxic intercellular molecules, such as superoxide anions, nitric oxide, hydroxyl radicals, lysozyme. Can also present processed antigens to B and T cells.

30. Activated macrophages secrete G-CSF and GM-CSF Induce the division of Myeloid Precursors in bone marrow Releases Neutrophils into blood stream

31. Neutrophils normally circulate into blood stream and to enter a site of inflammation, a neutrophil undergoes a complex process consisting of :- Margination Rolling Adhesion Diapedesis Neutrophils then phagocytose organisms and kill them in 2 methods :- Oxygen dependent ( Respiratory burst) Oxygen independent

32. NETs : Neutrophils release Neutrophil extracellular traps (NETs) that are composed of Extracellular strands of DNA bound to Neutrophil derived AMPs and proteins. During the course of NET production, neutrophils lose their nulcei and die. Nuclear chromatin present in NETs that includes histones and associated DNA is postulated to be a source of nuclear antigens in autoimmune diseases such as lupus.

33. EOSINOPHILS :- Protect the body from parasites (nematodes) Infection Production of antigen specific IgE antibodies Eosinophils bind to IgE and become activated Release toxic products like MBP, ECP, Eosinophil Peroxidase Also play a role in allergic reactions.

34. THE MAST CELL :- 2 types :- 1. MC tc 2. MC t Because different kinds of mast cells are involved in urticaria and anaphylaxis, the manifestations due to activation of either are different. Both MC tc and MC t have F CE RI receptors (high affinity IgE receptors) Mast cells have an important role in urticaria, angioedema and contact hypersensitivity reactions. PARAMETERS MC tc MC t Locations Skin and Submucosa Alveoli and Nasal mucosa Enzymes Trypsin and Chymase Trypsin only

35. PRO-INFLAMMATORY MEDIATORS :- Mast cells have multiple preformed mediators of inflammation – most important being HISTAMINE. 2 types PREFORMED MEDIATORS Histamine Heparin Proteases, e.g. trypsin NEWLY FORMED MEDIATORS PGD 2 Platelet activating factor Leukotrienes [LTC4, LTD4, LTE4]

36. NATURAL KILLER CELLS :- Eliminate virally infected or malignant cells. Do this in 2 ways ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY KILLER ACTIVATING & KILLER INHIBITORY RECEPTORS NK Cells have receptors for IgG. So these then adhere to target cells coated with IgG and then kill them. Killer Activating receptors recognise molecules expressed by nucleated cells and then NK cells secrete perforins leading to production of holes in cell membrane through which granzymes are injected.

37. SECTION 4 ADAPTIVE IMMUNE RESPONSE

38. ADAPTIVE IMMUNE RESPONSE LANGERHANS CELLS :- Derived from bone marrow. Langerhans cells are associated with nerve fibres ; and nerves, by release of CGRP ( Calcitonin gene related peptide) can modulate function of LCs. Cannot be appreciated on routine H&E. Recognition requires electron microscopy or histochemical analysis. Ultrastructurally , Birbeck granules ( rod shaped granules) are seen.

39. Activated Langerhans cells Elongate their dendrites Dendrites penetrate into tight junctions between keratinocytes & survey the area just below Stratum corneum for Antigens Penetrating dendrites take up antigens Then keratinocytes rapidly close these defects and thus maintain skin integrity MARKERS OF LANGERHANS CELLS :- CD 207 [LANGERIN], CD45 [PANHEMATOPOEITIC MARKER], CD1a, S100, Vimentin.

40. DENDRITIC CELLS :- Antigen presenting cells with high capacity to stimulate naïve T cells and stimulate an innate immune response. Derived from peripheral blood. Lymphoid/plasmacytoid dendritic cells stimulate Th2 response. Myeloid dendritic cells induce Th1 response, However the type of immune response generated also depends on the state of maturation of the dendritic cell i.e. Presence of IL 12 is necessary to induce a Th1 response and usually it is always present when a DC is activated, which means that if at this stage, a T cell comes in contact with the DC, it will be converted to a Th1 cell. It is at a later stage, that when IL 12 decreases, Th2 response gets favoured.

41. T CELLS Lymphocytes that mature in the T hymus are referred to as T lymphocytes Lymphocytes that mature in the B one marrow are referred to as B lymphocytes T HELPER CELLS :- CD4+ cells Naïve T cells can only produce IL 2 Their cytokine pattern becomes more specific as they differentiate into Th1, Th2 or Th17

42. Th1 Cells Typical cytokines are INF gamma, TNF alpha, IL 2 IL 2 production by these cells leads to stimulation of both Cytotoxic and helper T cells. INF gamma production leads to activation of macrophages to kill intracellular microbes.

43. Macrophages induced by IL 2 produce large amounts of IL 12 which induces Naïve t cells to Th1 phenotype. The second most important cytokine in promoting Th1 differentiation is TNF-α. Augmenting the antitumor response of Th1 cells represents a potential target of cancer immunotherapy. However, Th1 cells also contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, allergic contact dermatitis and psoriasis.

44. Th2 Cells Th2 cells produce primarily IL-4, IL-5, IL-6 and IL-10. IL-4 stimulates B cells to produce IgE, and IL-5 promotes the growth of eosinophils. Therefore, Th2 responses are associated with allergic diseases. Just like IL-12 is to inducing Th1 responses, IL-4 is to driving Th2 responses. In addition, IL-4 suppresses Th1 and Th17 differentiation. However, IL-4 seems to exert opposing effects on CD4+ T cells and DCs, since it can stimulate DCs to produce IL-12 and thus paradoxically promote Th1 development. IL-10 also inhibits the development of a Th1 response.

45. Immune responses generally tend to drift into a Th1, Th2 or Th17 pattern. IL-12 stimulates CD4+ T cells to produce IFN-γ and therefore leads to Th1 response. Many TLR signals and infections are strong inducers of IL-12 and therefore favor a Th1 response. Similarly, early production of IL-4 favor the generation of Th2 cells. Acute allograft rejection, allergic contact dermatitis, and multiple sclerosis are characterized by dominant Th1 responses. On the other hand, Th2 cells can be isolated from patients suffering from atopic dermatitis or systemic lupus erythematosus.

46. Th17 Cells :- “CD4+ T cells that produce IL-17, but neither IFN-γ nor IL-4 (and therefore do not fit into the Th1–Th2 spectrum), are referred to as Th17 cells.” Besides IL-17A, these cells also secrete IL-17F, IL-21 and IL-22. The IL-12-related cytokine IL-23 is essential for the generation of Th17 cell. IL-6 and IL-23 enhance the expression of IL-17 and IL-22 and suppress production of IL-10 and IFN-γ, thereby stabilizing the Th17 phenotype. IL-21 is also produced in large amounts by mature Th17 cells and amplifies Th17-cell differentiation.

47. Th17 cells are rapidly induced in response to infectious agents – in particular, bacteria and fungi. Patients with a defective Th17 response due to mutations in the gene encoding signal transducer and activator of transcription 3 (STAT3), have hyperimmunoglobulin E (hyper-IgE) syndrome and suffer from recurrent Candida albicans and Staphylococcus aureus infections of the skin and lung . Th17 responses have important roles in chronic inflammation and in mediating autoimmune reactions. Th17 cells are involved in rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases. Since IL-23 enhances IL-17 production, inhibition of IL-23 is a target for therapeutic intervention.

48. Th22 cells A subset of human CD4+ Th cells that is characterized by the secretion of IL-22 and TNF-α (in the absence of IFN-γ, IL-4 or IL-17) have been referred to as Th22 cells. IL-22 induces the expression of antimicrobial peptides (e.g. S100 proteins, defensins) as well as inflammatory chemokines and cytokines including IL-6. IL-22 is also involved in tissue repair by inducing epithelial cell proliferation and enhancing cell survival. IL-22 and Th22 cells appear to play an important role in psoriasis since IL-22 is highly expressed in psoriatic plaques.

49. Th3 cells: Th3 cells primarily secrete TGF-β, provides help for IgA production, and has suppressive properties against both Th1 and Th2 cells

50. CYTOTOXIC T CELLS :- Cytotoxic T (Tc) cells are CD8+. Recognize “their” antigens in association with MHC class I molecules, and can directly lyse their targets (e.g. virally infected or tumor cells). Tc cells have at least three different pathways of killing, two of which involve direct contact with the target cell. In one method, Tc cells insert perforins into the membrane of the target cell; this creates pores in the membrane, through which granzymes are released from the Tc cell into the target cell. Granzymes then activate caspases, which are proteolytic enzymes that induce apoptosis in the target cell. In a second mechanism, Tc cells activate the death receptor Fas (CD95) on the target cell by expressing the cognate death ligand FasL (CD95L). The activated Fas also triggers apoptosis in the target cell. The third pathway is mediated by cytokines, including TNF-α and IFN-γ. Naive CD8+ T cells (Tc0 cells) can develop into Tc1 and Tc2 cells.

51. NK T CELLS :- NK T cells are a distinct subset that have characteristics of both T cells and NK cells. They express the NK marker NK1.1 and CD1d. NK T cells produce large amounts of various cytokines, including IFN-γ, IL-4, and IL-10. They are thought to be involved in the differentiation of various T-cell subsets, especially Th2 cells. They may also play a role in the control of autoimmunity, since NK T cells are numerically and functionally deficient in mice with autoimmune diseases. NK T cells also seem to contribute to UV-induced immunosuppression, and they down-regulate immune responses to UV-induced tumors. γ/δ T cells Dendritic epidermal T cells

52. MALT & SALT SALT Stands for Skin associated Lymphoid Tissue . MALT Stands for Mucosa associated Lymphoid Tissue . Diffuse collections of lymphoid tissue in various submucosal locations in body MALT is populated by lymphocytes, macrophages, plasma cells and dendritic cells. In case of the intestine, M cells are also present that sample antigen from the lumen and deliver it to lymphoid tissue. MALT constitutes about 50% of total lymphoid tissue in body.

53. MALT can also be differentiated on basis of level of organisation of tissue :- 1. O MALT :- O rganised Mucosa Associated Lymphoid Tissue E.g. Tonsils of Waldeyer’s Ring D MALT :- D iffuse Mucosa Associated Lymphoid Tissue Not organised as a separate anatomically identifiable mass, tissue or organ

54. ROLE IN DISEASES :- MALT has a role in mucosal immunity. It can be site of lymphomas, usually non Hodgkin lymphomas . A specific entity is Marginal zone B cell lymphoma , associated with Helicobacter pylori infection.

55. B CELLS & ANTIBODIES Main function of B cells is in development of immunoglobulins, which Prevent antigens from adhering to mucosal surfaces Activate complement Opsonise bacteria.

56. ANTIGEN :- Any substance that satisfies 2 immunological properties :- Immunogenicity : Ability of an antigen to induce an immune response (B/T cell mediated) B cells + antigen = Effector B cells (Plasma cell) + Memory B cells T cells + antigen = Effector T cells (Cytotoxic/ Helper T cell) + Memory T cell Antigenicity : Also known as IMMUNOLOGICAL REACTIVITY. Ability of the antigen to combine with final products of above 2 responses [ i.e. antibodies or T cell surface receptors]

57. ANTIBODY :- An antibody is a Y shaped heterodimer Composed of 4 polypeptide chains --- 2 light chains and 2 heavy chains. All 4 chains are bound to each other by disulfide bonds All chains have 2 ends --- N terminal and C terminal. There are 5 classes of H chains & 5 classes of immunoglobulins. Light chains are of 2 types :- Kappa & Lambda. Both light chains in any antibody molecule are either Kappa or Lambda, never both.

58. CLASS OF ANTIBODY HEAVY CHAIN TYPE IgA Alpha IgD Delta IgE Epsilon IgG Gamma IgM Mu

59. ENZYMATIC DIGESTION OF ANTIBODY 1. PAPAIN DIGESTION : Leads to cleaving of the antibody molecule at a level ABOVE THE HINGE REGION into 2 Fab and 1 Fc fragments. The two Fab fragments are soluble fragments that bind to the antigen [Fab = Antigen binding fragment] Fc fragment is an insoluble fragment that gets crystallised when exposed to cold.

60. PEPSIN DIGESTION :- Pepsin digests at a level BELOW THE HINGE REGION into one F(ab’) fragment (2 Fab subunits bound together) and multiple smaller fragments due to breakdown of the Fc fragment by pepsin.

61. SECTION 5 GRANULOMATOUS INFLAMMATION

62. INTRODUCTION :- Definition : Chronic inflammation with collection of activated macrophages, T cells and central necrosis. Basically, it is a cellular attempt to contain an offending agent that is difficult to eradicate Strong activation of T cells Macrophage activation Develop abundant cytoplasm and resemble epithelial cells, also called epithelioid cells SOME ACTIVATED MACROPHAGES CAN FUSE TO FORM MULTINUCLEATED GIANT CELLS .

63. 2 types of granulomas FOREIGN BODY GRANULOMAS Relatively inert foreign bodies with almost absent T cell mediated response IMMUNE GRANULOMAS Multiple agents leading to stimulation of T cells (e.g. Persistent microbes or self antigen)

64. MORPHOLOGY OF A GRANULOMA :- EPITHELOID CELLS : Activated macrophages with indistinct cell boundaries GIANT CELLS : Multinucleated, large cells derived from fusion of multiple macrophages CASEOUS NECROSIS : Gross appearance is cheesy and granular.

65. 2 types of granulomas in dermatology :- INFECTIVE TUBERCULOSIS Leprosy Syphilis Fungal Infections : Histoplasmosis Coccidiomycosis Para coccidiomycosis Blastomycosis Sporotrichosis Chromoblastomycosis NON-INFECTIVE Sarcoidosis Granuloma annulare Cutaneous Crohn’s disease Necrobiosis lipoidica Actinic Granuloma Foreign body Granulomas

66. SECTION 6 JAK STAT PATHWAY

67. INTRODUCTION Janus kinases (JAK) are a family of 4 enzymes including JAK1,JAK2, JAK3 and TYK2. STAT (Signal transducer and Activator of Transcription) is a family of 7 receptors including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b & STAT6

68. Insert image to show working of JAK STAT pathway

69. ASSOCIATED DISEASES :- JAK3 loss of function mutation ---------------  SCID JAK2 gain of function mutations ------------- Polycythaemia vera Gain of function mutations in JAK ----------- Lymphomas STAT3 mutation ------------------------------------- Hyper IgE Syndrome TYK2 deficiency ------------------------------------- Recurrent respiratory infections

70. JAK STAT PATHWAY INHIBITORS FIRST GENERATION :- TOFACITINIB RUXOLITINIB BARICITINIB SECOND GENERATION :- UPADACITINIB FILGOCITINIB RESICOCITINIB ITACITINIB

71. INSERT 2 SLIDES MOBILE

72. SECTION 7 ALLERGIC CONTACT HYPERSENSITIVITY

73. INDUCTION :- Present Antigen to Naïve T cells Clonal expansion Effector T cells Released in circulation HAPTENISATION : Conversion of generally low molecular weight contact allergens into full Antigens after coupling with host proteins. This process is called haptenization. The low molecular weight allergen is called hapten . Application of hapten to a naïve host APCs (LC/ dDC ) in skin take up hapten Migrate to regional Lymph node

74. During emigration from Skin to Lymph Node, APCs convert from inactive to functional state influence of inflammatory cytokines released by keratinocytes Further, inflammasome in keratinocytes get stimulation, by contact sensitisers `IL 1 beta & IL 18 production Induction of IL 1 beta is specific to haptens (not seen with tolerogens/ contact irritants) Hapten itself via its capacity to produce a specific cytokine provokes APCs and stimulates sensitisation. IN CONTRAST TO OTHER TYPES OF DELAYED HYPERSENSITIVITY RESPONSES, ALLERGIC CONTACT HYPERSENSITIVITY HAS CD8+ CELLS IN MEDIATION.

75. Also, T reg cells are also induced [that actually inhibit Contact Hypersensitivity]. However, it must be noted that the balance between effector T cells & T regulator cells depends on dose of antigen applied [ EXTREMELY LOW DOSE OF HAPTENS DOESNOT CAUSE SENSITISATION, BUT RATHER TOLERANCE].

76. ELICITATION :- T cells primed in draining cutaneous Lymph nodes express the SKIN HOMING MARKER {CLA} & thus exhibit the capacity to enter the skin. These cells get activated on encountering their relevant hapten presented by the APCs in skin However, now Ag presentation can be performed by other cells ( keratinocytes, mast cells & macrophages}, unlike the initiation phase.

77. KERATINOCYTES AS IMMUNE TARGETS & EFFECTORS KERATINOCYTES AS IMMUNE TARGETS Keratinocytes express MHC Class 1 molecules Prone to attack by CD8+ T cells MHC class 1 restricted T cell mediated cytolysis occurs; as can be seen in LICHEN PLANUS, FDE, CUTANEOUS GVHD & HERPES SIMPLEX INFECTION IFN Gamma stimulates keratinocytes Keratinocytes develop MHC class 2 molecules Activation of CD4 T cell line proliferation {but not naïve cells}

78. AS INITIATORS :- Keratinocytes can produce IL1 & 10 upon stimulation by large amounts of Interferon gamma which will lead to autoimmunity. Langerhans cells via CD40/CD40L interactions stimulate keratinocytes ; which further stimulates Langerhans cells and leads to their migration to lymph node and in experimental models have been shown to lead to lupus like condition.

79. BIBLIOGRAPHY The content for this presentation has been taken from : Bolognia Textbook of Dermatology Edition 4 Robbins and Cotran Pathologic Basis of Disease Edition 9 Rook’s Textbook of Dermatology Edition 9 Comprehensive Drugs in Dermatology Edition 4 (Wolverton) Review of Medical Microbiology and Immunology Edition 17 (Levinson) Essentials of Medical Microbiology Edition 3 (Apurba Sastry & Sandhya Bhat) First Aid for USMLE Step One Special Indian Edition Google images Wikipedia