Acquired Immune Response Sanjaya Adikari Department of Anatomy

Immune Response Defense against foreign invaders or cancer cells Immune Response Innate ResponseAcquired Response Antibody Response Cell mediated Response

Innate Response Adaptive Response

Cells of the immune system

Properties of Immune cells Inactive/Naive Activated cells Effector cells Few surface molecules Many surface molecules Becomes larger in size Proliferate and produce more cells Release peptides and lipids Increased ability to migrate

Macrophage epithelium

Macrophage Common receptors for immune cells of many animals Detect pathogen associated molecular patterns

Macrophages Opsonization by Complement proteins epithelium Toll-like receptor

Toll-like receptors Pathogen-associated molecular patterns

Phagosome Lysosomes Phagolysosome H 2 O 2 O 2 - NO Activated macrophage Prostaglandins, Leukotrienes and Platelet activating factor

Flow increased Velocity reduced Lipid mediators of inflammation Increased diameter Increased permeability

Increased expression of adhesion molecules

Phagosome Lysosomes Phagolysosome H 2 O 2 O 2 - NO Activated macrophage Chemokines Cytokines

Proteins released by cells that affect the behavior of other cells that bear receptors for them Chemokines Proteins released by cells that attract other cells that bear receptors for them A A

Neutrophil H 2 O 2 O 2 - NO

Body tissue

activated Cytokines Mediators of Chemokines Mediators of infl. Cytokines Chemokines Cytokines Chemokines

Pus cells

Natural Killer cells Also called NK T cells Larger than T and B cells Activated during the innate response by macrophage derived cytokines Eg. IL-12 and Interferons Produce IFN-  when activated Kills cells infected with intracellular pathogens Mechanism of Killing is similar to that of cytotoxic T cells

Complement system Augments the opsonization of bacteria by antibodies. Hence, the name, meaning that it complements the antibodies Large number of plasma proteins that react with each other following a trigger Most of them are proteases that are themselves activated by proteolytic cleavage

Complement system….cont. Precursor proteins are widely distributed in body fluids and tissues Only activated on the surface of the pathogens Once triggered it becomes a huge reaction in its successive steps

Trigger

Innate immunity - summary Immune cells identify the ‘pathogen-associated molecular patterns’ on the cell membrane of pathogens Pathogen is immediately destroyed Neutrophils and macrophages are key players Complement system plays an important role Activated dendritic cells present antigens

Kill Body cells

Kill Body cells

From Innate to Adaptive Cells activated during the innate immune response bridge the gap between the innate and the adaptive systems Dendritic cells and Macrophages

Adaptive Immune Response

Dendritic cells epithelium

T T T Antigen presentation Antigen presenting cells (APC) Toll-like receptors T T Dendritic cell or macrophage Clonal expansion of lymphocytes

Dendritic Cells (DC) Most potent APC (>>> macrophages) Designated as professional APC Main function is to control T and B cells through presentation of different antigens

T B T B T B Mature DC T T Immature DC Circulation T B T B T B T B T B T B

Jefford et al., Lancet, June 2001

Surface molecules on DC and T cells Cell-cell interaction molecules Receptors for cytokines Receptors for chemokines Cell adhesion molecules

B7= CD80 & CD86 MHC I B-7 MHC II Antigen presenting cell Cell-cell interaction molecules on DC and T cells TCR CD8 CD28 TCR CD4 CD28 CD4 + helper T cell CD8 + cytotoxic T cell

MHC molecules Two types: MHC type I and MHC type II MHC type I: Expressed in all body cells MHC type II: Expressed in some immune cells Dendritic cells, macrophages and B cells Human counterpart is called HLA MHC – Major histocompatibility complex HLA – Human leukocyte antigen

DC-T cell interaction 1 st signal – determines antigen specificity 2 nd signal – triggers T cell proliferation Dendritic cells send two signals to T cells

TCR CD4 + helper T cell CD4 MHC II immature DC 1 st signal

TCR CD4 CD28 B-7 Increase proliferation MHC II mature DC 2 nd signal CD4 + helper T cell Secrete IL-2 (growth factor of T cells)

TCR CD8 + cytotoxic T cell CD8 MHC I immature DC 1 st signal

TCR CD8 CD28 B-7 Increase proliferation MHC I mature DC 2 nd signal CD8 + cytotoxic T cell Secrete IL-2

B7= CD80 & CD86 MHC I B-7 MHC II Antigen presenting cell Cell-cell interaction molecules on DC and T cells TCR CD8 CD28 TCR CD4 CD28 CD4 + helper T cell CD8 + cytotoxic T cell

MHC I MHC II APC TCR CD8 TCR CD4 Vesicle Cytoplasm Intravesicular pathogens Extracellular pathogens Toxins

T helper cells (Th cells) Th1 cells Th2 cells Th0 cells

Cytokines Th1 cells IFN-  Cytokines Th2 cells IL-4 IL-5 IL-10 Macrophage ActivationB cell Activation

Th1 cells Produce IFN- , the main macrophage-activating cytokine. It inhibits B cells Th2 cells Produce IL-4, IL-5 that activates B cells and IL-10 that inhibits macrophages Th0 cells Produce both Th1 and Th2 cytokines and therefore have a mixed effect

Mycobacterium leprae grows in macrophage vesicles. Clinical relevance of Th1 vs Th2 To destroy bact. need to activate macrophages by Th1 cells Th2 response is a waste Th1 response Tuberculoid leprosy - Few live bacteria - Little Ab in serum - Skin & PN damage due to Mac. activation - Slow disease, patient survives Th2 response Lepromatous leprosy - Numerous live bacteria - Lot of Ab in serum (ineffective) - Gross tissue damage & death

Humoral immune response

MHC II B cell BCR

MHC II BCR

MHC II BCR

MHC II TCR CD4 CD4 + T helper cell B cell IL-4 IL-5 IL-6 IL-10 Th2

B cell Plasma cell Ab mediated response (Humoral immunity) IL-4, IL-5, IL-10

MHC II TCR CD4 CD4 + T helper cell B cell IFN-  Th1 Inhibition

Cell mediated response

TCR CD8 + cytotoxic T cell CD8 MHC I immature DC 1 st signal

TCR CD8 CD28 B-7 Increase proliferation MHC I mature DC 2 nd signal CD8 + cytotoxic T cell Secrete IL-2

TCR CD8 MHC I mature DC effector CD8 + cytotoxic T cell Infected Tissue Kill IFN- 

Activate Macrophages effector CD4 + Th1 cell

Macrophages

CD4 T cells CD8 T cells cytokines chemokines Kills virus or intracellular pathogen infected body cells MHC I MHC II cytokines chemokines B cells Cell mediated response Antibody mediated response Immunological memmory

Immunological memory The ability of the immune system to respond more rapidly and effectively to pathogens that have been encountered previously Both T cells and B cells are left behind as memory cells following the primary immune response These are a distinct populations of long lived cells, without the need to getting exposed to residual antigen, in the body

Immunological memory…cont. In the presence of memory T and B cells, the naïve T and B cells are not activated upon exposure to the same antigen again (would be a waste)

Adaptive immunity - summary The immune cells need to specifically identify the pathogen Clonal expansion of specific immune cells Takes few days to build up T and B lymphocytes are key players Leaves behind memory cells

TCR T cell CD4 CTLA-4 _ Suppress proliferation B-7 CD28 B-7 + Increase proliferation HLA II Immature DC Mature DC autoantigens T cell annergy Immature DC