INNATE IMMUNITY CELLULAR INNATE IMMUNITY CELLS INVOLVED IN

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INNATE IMMUNITY

INNATE IMMUNITY

CELLULAR INNATE IMMUNITY

CELLULAR INNATE IMMUNITY

CELLS INVOLVED IN THE INNATE IMMUNE SYSTEM Polymorphonuclear Leukocytes “PMNLS”, “granulocytes”. Ø Basophils Ø

CELLS INVOLVED IN THE INNATE IMMUNE SYSTEM Polymorphonuclear Leukocytes “PMNLS”, “granulocytes”. Ø Basophils Ø Mast cells Ø Eosinophils Ø Neutrophils Monocyte and macrophage Innate lymphoid cells Mast cell Dendritic cell

CELLS INVOLVED IN THE INNATE IMMUNE SYSTEM They contain the enzyme – rich lysosomes.

CELLS INVOLVED IN THE INNATE IMMUNE SYSTEM They contain the enzyme – rich lysosomes. They produce peroxide and superoxide radicals which are toxic to many microorganisms Some lysosomes contain bactericidal proteins, such as lactoferrin. Defects in PMN cell function are accompanied by chronic or recurrent infection Some of them have a major role in antigen detection and presenting

PHAGOCYTES v Neutrophils are produced at a rate of 7 million per minute and

PHAGOCYTES v Neutrophils are produced at a rate of 7 million per minute and released from bone marrow. They are short –lived “ 2 -3 days” They represent 95% of the circulating granulocytes.

v Neutrophils are the first white blood cells recruited to sites of acute inflammation,

v Neutrophils are the first white blood cells recruited to sites of acute inflammation, in response to chemotactic cues such as CXCL 8 (interleukin-8, IL-8) produced by stressed tissue cells and tissue-resident immune cells such as macrophages. v Neutrophils therefore comprise a large proportion of the early cellular infiltrate in inflamed tissues and are the major constituent of pus.

 They contain antibiotic proteins which are stored in two main types of granules:

They contain antibiotic proteins which are stored in two main types of granules: 1 - The primary “azurophilic “ granules, they are lysosomes containing acid hydrolases , myeloperoxidase, lysozyme, defensins and bacterial permeability inducing protein ”BPI”. 2 - The secondary granules “ specific to neutrophils” contain lactoferrin and lysozyme. v Other small granules contain gelatinase v Neutrophils can also release granules and cytotoxic substances extracellularly when they are activated by immune complexes through their Fc receptors.

NEUTROPHIL UNDER ELECTRON MICROSCOPE

NEUTROPHIL UNDER ELECTRON MICROSCOPE

v. Macrophages: They are phagocytes derived from blood monocytes. Have different names: Kupffer cells,

v. Macrophages: They are phagocytes derived from blood monocytes. Have different names: Kupffer cells, in the liver. Alveolar macrophages, in the lung. Splenic macrophages, in the white plup. Peritoneal macrophages, free floating in peritoneal fluid. Microglial cells, in the central nervous system.

TWO MAIN PATHWAYS OF MACROPHAGE: REVERSE ACTION

TWO MAIN PATHWAYS OF MACROPHAGE: REVERSE ACTION

ENDOCYTOSIS It is the ingestion of macromolecules present in extra cellular tissue fluid. This

ENDOCYTOSIS It is the ingestion of macromolecules present in extra cellular tissue fluid. This occurs either by nonspecific membrane invagination or by receptor mediated endocytosis with endocytic vesicle – endosomelysosomes yield breakdown products.

PHAGOCYTOSIS The ingestion of invading particles e. g. bacteria – by phagocytic cells. Phagocytosis

PHAGOCYTOSIS The ingestion of invading particles e. g. bacteria – by phagocytic cells. Phagocytosis is aided by opsonins “antibodies, complement components”. The foreign particle is entrapped in a phagocytic vacuole.

INTRACELLULAR KILLING Oxygen dependent Myeloperoxidase dependent H 2 O 2 + Clmyeloperoxidase - 2

INTRACELLULAR KILLING Oxygen dependent Myeloperoxidase dependent H 2 O 2 + Clmyeloperoxidase - 2 OCL + H 2 O OCl- + H 2 O 1 O -+ Cl-+ 2 - 2 O 2 + 2 H+ Superoxide dismutase 2 H 2 O 2 catalase H 2 O 2 + O 2 H 2 O + O 2 -

 Oxygen dependent Myeloperoxidase independent Glucose +NADP+ G-6 -P-dehydrogenase NADPH + O 2 Cytochrome

Oxygen dependent Myeloperoxidase independent Glucose +NADP+ G-6 -P-dehydrogenase NADPH + O 2 Cytochrome b 558 Pentose-P + NADPH + NADP + O 2 - - 2 O 2 + 2 H+ Superoxide dismutase - 2 O 2 + H 2 O 2 Oxygen independent H 2 O 2 + 1 O 2 . OH + OH- + 1 O 2

v Innate lymphoid cells (ILCs) are a group of innate immune cells that belong

v Innate lymphoid cells (ILCs) are a group of innate immune cells that belong to the lymphoid lineage but do not respond in an antigen-specific manner, as they lack a B or T cell receptor. ILCs do not express myeloid or dendritic cell markers. Classified at the first time in 2013 according to transcriptional factors and cytokine release into three groups : Group 1 ILCs or ILCs 1 : can produce type 1 cytokines (notably IFNγ and TNF) and comprise NK cells and ILC 1 s. analogous to Th 1 and cytotoxic T cells (tumor and viral clearance). ILC 1 s are weakly cytotoxic cells closely related to ILC 3 s. Raise Natural killer ('NK') cells

Group 2 ILCs Can produce type 2 cytokines (e. g. IL-4, IL-5, IL-9, IL-13).

Group 2 ILCs Can produce type 2 cytokines (e. g. IL-4, IL-5, IL-9, IL-13). Also termed natural helper cells, nuocytes, or innate helper 2 cells. analogous to Th 2 cells ( helminthic infection). Group 3 ILCs defined by their capacity to produce cytokines IL-17 A and/or IL-22. Raise Lymphoid tissue inducer ('LTi') cells essential for development of lymphoid organs during embryogenesis and after birth analogous to Th 17 cells (Enteric pathogens clearance, lymphoid tissue development, memory T cells maintenance)

Spits, et al. , 2013

Spits, et al. , 2013

v Dendritic cells Long lived, reside in an immature state in most tissues They

v Dendritic cells Long lived, reside in an immature state in most tissues They recognize and phagocytize pathogens and other antigens. They are found as inter digitating cells of the thymus and Langerhans cells in the skin. They are derived from the same hematopoietic precursor cells as monocytes. Direct contact with many pathogens leads to the maturation of dendritic cells and increasing their antigen presenting capacity such maturation allows them to activate naïve antigen specific T-cells. Thus they are important in both innate immunity and the initiation of adaptive immune responses.

v Natural killer cells : a lymphocyte able to bind to certain tumour cells

v Natural killer cells : a lymphocyte able to bind to certain tumour cells and virus-infected cells without the stimulation of antigens, and kill them by the insertion of granules containing perforin They lack TCRs NK cells express non – TCR – related receptors called killer cell inhibitory receptors (KIR) which bind to MHC class I molecules. Killing is achieved by the release of various cytotoxic molecules, some of these cause the pore formation on the membrane of target cells, leading to its lysis, other molecules enter the target cell and cause apoptosis.

 Functions Killing infected cells (cytotoxic) Secretion of cytokines Activation by Type 1 interferons

Functions Killing infected cells (cytotoxic) Secretion of cytokines Activation by Type 1 interferons Infected cells Stimulates cytotoxic function IL-12 and TNF-alpha Macrophages Stimulates cytokine secretion

FUNCTIONS OF NK CELLS

FUNCTIONS OF NK CELLS

 Activated NK cells release IFN-gamma and IL-12 which activates macrophages Differentiate infected from

Activated NK cells release IFN-gamma and IL-12 which activates macrophages Differentiate infected from uninfected cells NK cells express receptors for MHC class I molecules Binding of NK cells to MHC class I molecules turn off NK cells provide innate immunity to intracellular pathogens v NK cells vs NKT cells are NOT the same as NK cells. NKT cells are T cells with an αβ TCR. However, they also express some of the cell-surface molecules of NK cells — hence their name

Functions of activating and inhibitory receptors of NK cells

Functions of activating and inhibitory receptors of NK cells

SO HOW ALL THESE CELLS RECOGNIZE DIFFERENT ANTIGENS? ?

SO HOW ALL THESE CELLS RECOGNIZE DIFFERENT ANTIGENS? ?

PATTERN RECOGNITION RECEPTORS (PRRS) The interaction with the pathogen can be direct by pattern

PATTERN RECOGNITION RECEPTORS (PRRS) The interaction with the pathogen can be direct by pattern recognition receptors (PRRs), or indirect, through recognition of opsonised microbes by Fc receptors or complement receptors. PRRs play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells.

PATTERN RECOGNITION RECEPTORS (PRRS) PRR identify two classes of molecules: Pathogen-associated molecular patterns (PAMPs),

PATTERN RECOGNITION RECEPTORS (PRRS) PRR identify two classes of molecules: Pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens. Damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

 PRRs devided into three classes : Membrane-bound PRRs : Receptor kinases Toll-like receptors

PRRs devided into three classes : Membrane-bound PRRs : Receptor kinases Toll-like receptors (TLR) C-type lectin Receptors (CLR) Cytoplasmic PRRs : multifunctional ! ! DS viral DNA, gram negative peptedoglycan, apoptosis … Secreted PRRs : Complement receptors, collectins (as MBL), pentraxins (as CRP)

TOLL – LIKE RECEPTORS "TLRS": Each recognizes specific microbial components. Activation of TLRs by

TOLL – LIKE RECEPTORS "TLRS": Each recognizes specific microbial components. Activation of TLRs by microbial components leads to activation of the innate immunity as well as adaptive immunity through production of cytokines and expression of co simulators molecules. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, noncatalytic receptors usually expressed on many immune cells to recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR 1, TLR 2, TLR 3, TLR 4, TLR 5, TLR 6, TLR 7, TLR 8, TLR 9, TLR 10, TLR 11, TLR 12, and TLR 13, though the latter three are not found in humans. TLR's received their name from their similarity to the protein coded by the toll gene identified in Drosophila.

TLRS: LOCATION AND TARGET

TLRS: LOCATION AND TARGET

DIFFERENT TLRS CAN RECOGNIZE DIFFERENT ANTIGENS AS LISTED BELOW TLR-1: - Bacterial lipoprotein and

DIFFERENT TLRS CAN RECOGNIZE DIFFERENT ANTIGENS AS LISTED BELOW TLR-1: - Bacterial lipoprotein and peptidoglycans TLR-2: - Bacterial peptidoglycans TLR-3: - Double stranded RNA TLR-4: - Lipopolysaccharides TLR-5: - Bacterial flagella TLR-6: - Bacterial lipoprotein TLR-7: - Single stranded RNA TLR-8: - Single stranded RNA TLR-9: - Cp. G DNA TLR-10: - Unknown

RECOGNITION OF MICROBES AND DAMAGED SELF BY THE INNATE IMMUNE SYSTEM

RECOGNITION OF MICROBES AND DAMAGED SELF BY THE INNATE IMMUNE SYSTEM

CELLULAR LOCATION OF PATTERN RECOGNITION MOLECULES OF THE INNATE IMMUNE SYSTEM

CELLULAR LOCATION OF PATTERN RECOGNITION MOLECULES OF THE INNATE IMMUNE SYSTEM

TLRs are essential for innate cell specificity in infection fighting. Example: neutrophils have no

TLRs are essential for innate cell specificity in infection fighting. Example: neutrophils have no TLR 3 so they are not efficient in fighting ds. RNA viruses.

OTHER RECEPTORS INVOLVED IN THE INNATE IMMUNE SYSTEM: v F-met-Leu-phe receptor on neutrophils: A

OTHER RECEPTORS INVOLVED IN THE INNATE IMMUNE SYSTEM: v F-met-Leu-phe receptor on neutrophils: A chemotactic receptor that binds the N-formylated peptides of certain bacteria and guides neutrophils to the site of infection v Mannan - binding "MB" lectin: These enable phagocytes to recognize pathogenic microbe – expressed polysaccharides. Ligation of the phagocyte MB lectin “receptor” with these sugars initiated and activated the MB lectin pathway of complement. v Scavenger receptors: Receptors on phagocytes recognize specific anionic polymers expressed by certain pathogens and old dying RBCs, leading to the removal of these cells.

INDIRECT INTERACTION WITH MICROBES THROUGH RECOGNITION OF OPSONISED MICROBES BY FC RECEPTORS OR COMPLEMENT

INDIRECT INTERACTION WITH MICROBES THROUGH RECOGNITION OF OPSONISED MICROBES BY FC RECEPTORS OR COMPLEMENT RECEPTORS

HUMERAL INNATE IMMUNITY: THE COMPLEMENT SYSTEM

HUMERAL INNATE IMMUNITY: THE COMPLEMENT SYSTEM

COMPLEMENT SYSTEM • It consider as part of innate immune system. • Components that

COMPLEMENT SYSTEM • It consider as part of innate immune system. • Components that provide activity of blood serum that completes the action of antibody. The proteins and glycoproteins are synthesized mainly by hepatocytes. Most circulate in the serum in functionally inactive forms: proenzymes, or zymogen. They are activated by proteolytic cleavage; which removes an inhibitory fragment and exposes the active site. Heat-labile component of serum. The complement system is not adaptable and does not change over the course of an individual's lifetime.

KEY COMPONENTS OF THE COMPLEMENT SYSTEM Complement components are designated by numerals (C 1–

KEY COMPONENTS OF THE COMPLEMENT SYSTEM Complement components are designated by numerals (C 1– C 9), by letter symbols (e. g. , factor D), or by trivial names (e. g. , homologous restriction factor) Peptide fragments formed by activation of a component are denoted by small letters In most cases, the smaller fragment resulting is designated “a” and the larger fragment designated “b” • Ex: C 3 a, C 3 b • C 2 is an exception: C 2 a is the larger cleavage fragment The larger fragments bind to the target near the site of activation The smaller fragments diffuse from the site and can initiate localized inflammatory responses by binding to specific receptors Fragments interact with one another to form functional complexes Complexes that have enzymatic activity are designated by a bar over the number or symbol (e. g. , C 4 b 2 a, C 3 b. Bb)

ACTION OF THE COMPLEMENT SYSTEM The triggering and amplification of inflammatory reactions. Attraction of

ACTION OF THE COMPLEMENT SYSTEM The triggering and amplification of inflammatory reactions. Attraction of phagocytes by chemotaxis Clearance of immune complexes Cellular activation Direct microbial killing An important role in the development of antibody responses.

C 1 protein

C 1 protein

COMPLEMENT REGULATION There are several levels of regulation of the complement system: First :

COMPLEMENT REGULATION There are several levels of regulation of the complement system: First : the specific binding of the C 1 qr 2 s 2 complex to antigen-bound, cellbound antibody. This ensures that complement is not activated by random contacts between soluble antibodies and complement components. Second regulation relates to the short half life and limited stability of a number of the complement components once they have been produced in their active form. Thirdly a number of specific regulator proteins exist that block specific steps of the activation pathways or MAC activity. Finally Fourth, other proteins such as HRF and MIRL (CD 59) block the final assembly of the pore by preventing binding of C 9.

Note : The activity of many complement regulatory proteins is species-specific.

Note : The activity of many complement regulatory proteins is species-specific.