ADAPTIVE IMMUNE SYSTEM- Antigen presenting cells.pptx

ADAPTIVE IMMUNE SYSTEM- Antigen presenting cells.pptx

1. ADAPTIVE IMMUNE SYSTEM: Antigen presenting cells. DR. Nikunj patel

2. Characteristics of Adaptive immunity It initiates delayed and specific response against pathogenic insult. enhancement with each successive antigen encounter owing to the accumulation of cellular “memory”. Professional antigen-presenting cells (APCs), such as DCs and B cells, are specialized in capturing and displaying antigens to lymphocytes. Activation of T & B lymphocytes is done by antigen presenting cells in MHC restricted pattern.

3. CD8+ T cells recognize intracellular pathogens presented on MHC I by APC, which on activation cause cell lysis by perforin & granzyme release. They may also mediate caspase mediated apoptosis pathway. These cytotoxic T cells may secrete IFN-gamma and TNF -> antiviral and anti-tumor activity.

4. CD4 T cells are activated on extracellular antigen presentation in link with MHC-II on professional APC - DC, macrophages, and B-cells CD4 T cells may also drive B cell adaptive immunoglobulin response CD4+ T-helper cells consists of Th1, Th2 & Th17 Lymphotoxin and IL-12 stimulate Th1 IL4 stimulates Th2 IL23 stimulates Th17 and Th22

5. Th1 - Th2 imbalance can lead to immune inflammatory diseases. Th1 predominance : psoriasis Th2 predominance : atopic dermatitis Dysregulation of Th17 and Th22 : both Key difference between professional and non-professional APC : Presence of co-stimulatory molecule in APC and MHC-II based presentation to CD4+ T cells -> professional APC

6. Co- stimulatory molecules are CD40, CD80/86, ,ICOS (Inducible T cell COStimulator ) interact with their ligands CTLA4/CD28, CD40L, ICOSL, etc on lymphocytes to trigger adaptive immunity . Cross-presentation of antigen : DC that usually present exogenous Ag via MHC II can also present via MHC-I to CD8+T cells

7. DENDRITIC CELLS Potent inducers of naive & memory T cells activation and proliferation by presentation of non-self peptide MHC complexes. To induce T-cell central tolerance in thymus, DC present self peptide-MHC complexes . Immature DC are seen in circulation, when they reach tissue, get converted to mature DC (low PRR expression, express CD83 and CD91 along with other co-stimulatory molecules) Co stimulatory molecules like CD 40,CD 80/86,ICOS interact with ligands of CTLA4,CD40L,ICOSL on lymphocytes triggers adaptive immune response.

8. 2 main subsets of skin DCs : Conventional DCs of myeloid origin Dermal DCs Active NFkB signalling is necessary for steady state cutaneous migration of DC to draining lymph nodes. These migratory DC subsets induce either T-cell tolerance or T-cell priming and differentiation depending on the innate stimulus that stimulates DC maturation. They Secrete : IL-12,23,10 ; type I and II IFN Can also activate NK cells Tolerogenic DCs : immunoregulatory in function & control the function of T-reg cells

9. Type of immune response is dependent on the state of maturation of the stimulating DC at the time of antigen presentation. For the induction of Th1 responses, the presence of IL-12 is crucial. DCs tend to produce IL-12 directly after an activating step in their maturation, driving T cells into a Th1 phenotype if they meet the DCs at this stage At later time point, the production of IL-12 decreases, thereby favouring the development of a Th2 response. This process is also influenced by the innate immune system (e.g. stimulation by TLRs) and mast cells which can further skew T cells to produce Th1 and Th17 cytokines.

10. LANGERHANS CELLS The DC population which seed the epidermis before birth is derived from 2 embryonic sources : fetal liver , and to a minor extent, yolk sac Characteristics : Birbeck granules: rod-shaped organelles Which resembles tennis rackets. CD1a+, CD207+

11. Keratinocyte derived CSF1R ligand and IL-34 are required for migration and maintenance of langerhans cells to epidermis. Hair follicle keratinocytes induce langerhan cell immigration via CCL2 & CCL20 OR inhibit via CCL8 (thus act as portals of entry during times of stress ) Present lipid antigens and microbial fragments to activate CD8+ cells

12. Amplify immune response in allergic contact hypersensitivity and psoriasis Immune regulation and tissue homeostasis by causing T-reg cell expansion. Promote Th17 cell differentiation in response to extracellular pathogens like candida albicans. Histochemical visualization - staining for ATPase, a membrane bound, formalin resistant, sulfhydryl-dependent enzyme.

13. PLASMACYTOID DENDRITIC CELL ( pDCs ; CD123+). Important mediators of anti-viral immunity by producing type I IFN (IFN -alpha, beta) and can also detect self nucleic acids via endosomal PRRs (TLR 7,9) Type I IFNs trigger NK cells to produce IFN-gamma as well as B-cell differentiation Secrete : IL-12, 6 and TNF pDCs are significantly increased in patients with lupus erythematosus and psoriasis and further promote inflammation. Anti-tumor defense : kill tumor cells by granzyme & other cytolytic mechanisms

14. HIV infection : IFN production is efficient to facilitate pDC maturation and infected CD4 T-cell killing, but excess T-cell demise contributes to immune suppression. Imiquimod, a TLR7 and 8 agonist, enables pDC recruitment to dermis by CCR 6 dependent mechanism. It drives myeloid DCs to express perforin and granzyme B and drives plasmacytoid DCs to express TNF-related apoptosis-inducing ligand (TRAIL). This enables killing of tumor cells.

15. MONOCYTE-MACROPHAGE SYSTEM Monocytes are migratory cells of immune origin that traverse the circulatory system in search of cognate antigens On entering the peripheral tissues like skin and gut, get converted to macrophages. Main function – phagocytosis. Accessory function - antigen presentation. Autofluoroscent because of melanin granules.

16. MACROPHAGES IN SKIN M1 ( pro-inflammatory ) Phagocytic activity Secrete TNF,IL-12, Nitric Oxide to control intracellular pathogens by promoting granuloma formation in cases of mycobacteria and leishmania M2 (anti-inflammatory, proangiogenic ) Secrete VEGF which leads to increased lymphangiogenesis . Secrete IL-10 and TGF-B. IL-10 inhibits MHC II presentation on macrophages and decrease APC function of macrophages. IL-4 is important in pro-inflammatory CD14+ monocytes switch to M2 macrophage lineage(macrophage plasticity )

17. Wound healing macrophages IFN-gamma responsive CD163+ macrophages that express pro-inflammatory cytokines - detected in psoriatic skin . Also found in atopic dermatitis and CTCL.

18. MAJOR HISTOCOMPATIBILITY COMPLEX

19. MHC I presentation If the antigen has been produced endogenously within the cell (e.g. viral or tumor proteins), it is complexed with MHC class I molecules through intracellular processing pathways. The proteasome degrades cytosolic antigens produced by the cell. Resulting peptides (which consist of 8 to 12 amino acid residues) are then imported into the endoplasmic reticulum (ER) in a TAP (transporter associated with antigen processing)-dependent manner and loaded onto MHC class I molecules. After binding to the MHC class I– β2 micro- globulin complex, these peptides are transported to the cell surface via the Golgi apparatus. Alternative pathways by which exogenous proteins are phagocytosed with the phagosome fusing to the ER may also exist. The proteins would subsequently be re-transported out of the ER into the cytoplasm and then degraded by the proteasome. The degraded peptides could then enter the pathway that is normally employed for endogenous proteins via the TAP protein.

20. MHC II presentation MHC class II-associated antigen presentation targets primarily exogenous and less frequently endogenous antigens. Exogenous antigens are taken up via macro- or micropinocytosis or by receptor-mediated endocytosis Newly synthesized MHC class II molecules are associated with an invariant chain, which inhibits dissociation of empty MHC class II molecules and transports the MHC class II complex from the ER to the specialized endosomal compartments where the molecules can interact with antigen peptide fragments. In this compartment, the invariant chain is cleaved by proteases, leaving a small fragment called CLIP (class II-associated invariant peptide) that binds to the class II molecule. Upon interaction with the antigenic peptides, the CLIP fragment is released from the complex. The MHC class II molecule with the bound antigen peptide is subsequently expressed on the cell surface, allowing antigen recognition by T cells carrying the appropriate TCR.

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