Innate Immunity I, II تفريغ PDF

Block 1.1 lectures 2024-2025 lecture Highlighter key Writer 1 Reviser 1...

Block 1.1 lectures 2024-2025 lecture Highlighter key Writer 1 Reviser 1 >> Zahraa Albarraqi >> Doctor explanation Abbreviation Key information Book Zainab Adel Writer 2 Reviser 2 221-222-223 notes References Student explaintion Deleted >> >> Ali Alkhars Shahad Alshammary  Innate Immunity I,II BY Dr. Mervat Abdel-Aziz Medical Microbiology, Immunology & Infection Control  Structure of the Immune System The immune system is a mobile, circulating system. However, there are some fixed anatomical structures which are important to its function Immune System : 1- Innate immunity 2- specific acquired immunity ( adaptive )  For example, What are mature T cells ? Maturation means having markers on the T lymphocytes that migrated to the thymus surface of the cell after migrating to the site of gland ( their site of maturation ) and got maturation another cell surface markers ( CD3 ) 1- Primary lymphoid organ :lymphocyte formation and maturation A-Bone Marrow : Immune cells are formed within the bone marrow during the Bone marrow is the site of formation of all immune cells haematopoiesis process. in both innate & acquired immunity ( B lymphocyte / T lymphocytesm/ Natural killers … etc ) B- The thymus gland It is the site where lymphocytes get matured and receive their immunological “education” before being released into the bloodstream. : ‫طريقة لتسهيل الحفظ‬ B lymphocyte complete its maturation in bone marrow The maturation occurs at : while T lymphocyte complete its maturation in the B lymphocyte ——-> Bone marrow thymus gland ( B with B ) but both of them were formed in the bone marrow as all T lymphocyte ——-> Thymus gland the other immune cells ( T with T ) From the book  Maturation the cell will have markers on the surface of the cell after Definition migrating to the site of maturation T lymphocytes that migrated to the thymus For example gland ( their site of maturation ) and got another cell surface markers ( CD3 ) all immune cells in both innate & acquired immunity the site for maturation T lymphocyte B lymphocyte thymus gland bone marrow  After B & T cells become mature, they go to the secondary lymphoid organs and considered as “Naive cell” before they get functioning ( haven’t encountered their cognate antigens) 2- Secondary lymphoid organ (lymphocyte meet antigen and activation) Lymph node: Mature lymphocytes migrate to lymph nodes. These filter lymph and provide a site for antigen presentation to the adaptive immune system Lymph nodes are the site where both B & T cells get function ( effector cells ) The spleen is basically a massive lymph node and is, therefore, another site of antigen presentation to mature lymphocytes. (It is a part of the reticulo-endothelial system which filters blood and removes aging cells, tissue debris, pathogens and immune complexes. It also stores red blood cells and immature monocytes. The spleen is one of the most important organs of the immune system as a secondary lymphoid organ. In some chronic hemolytic anemia kids or even a normal kid who fell and had a ruptured spleen, they can only be treated by splenectomy but the spleen is a highly vascularized organ so the kids who had the surgery will have to take all the vaccines against the encapsulated organisms From the book  After cells get functional ( B & T lymphocytes ) they enlarge in size and become effector cells which explain the lymph node enlargement during some infections whyl ymph node enlarge during some infections? Because B & T lymphocytes enlarge in size and become effector How do the functioning immune cells ( effector cells ) know the exact site of infection ? by chemical signals called cytokines attract the effector cells to the site of infection  NB liver: also a site of antigen presentation and contains its own cohort of phagocytes and lymphocytes liver filters large volumes of potentially contaminated venous blood from the gastrointestinal (GI) tract. It also synthesizes acute phase proteins  Cells of the Immune System innate immune cells : 1- GRANULOCYTES (Family of white blood cells containing granules in their cytoplasm)  It has the highest number / percentage A- NEUTROPHILS normally make up 40-75% of all white blood cells (2000-7500 /cmm on a full blood count) The first line of defense against all infections act by phagocytosing invading organisms and presenting antigens to the immune system They are involved in all the infactions They have segmented nuclei and their cytoplasm is full of pinky-purple intracellular granules Very important cell because it normally exists in large amounut / number  2- EOSINOPHILS normally make up 1-6% of white blood cells (40-400 /cmm on a full blood count) specifically act against multicellular parasites (e.g. worms) by dissolving their cell surfaces they are also involved in IgE-mediated allergic disorders such as asthma they have bilobed nuclei and intracellular granules which stain brick red with eosin  C- BASOPHILS normally make up 0-1% of white blood cells (≤10 /cmm on a full blood count) They are the circulating counterparts of tissue mast cells. they may have roles in inflammation, parasitic infections and allergic reactions mast cells/basophils have an important role in type 1 hypersensitivity reactions through their binding with IgE antibodies they have bilobed nuclei and large darkly staining intracellular granules There are 4 types of hypersensitivity according to the involved cells and the involved antibodies. In type 1 hypersensitivity the cells involved are : Basophils & Eiosinophils and the antibody involved is : IgE  hypersensitivity they classify according to: involved cells involved antibodies type 1 hypersensitivity involved cells : Basophils & involved antibodies: IgE Eiosinophils  Adaptive immune cells : MONOCYTES & MACROPHAGES (Large cells involved in phagocytosis and antigen presentation). We have phagocytosis in Neutrophils & Macrophages, the difference is that : Macrophages are more efficient but Neutrophils are more important due to their high number ( count ) and their short lifespan ( about 3 days )  A-BLOOD MONOCYTES normally make up 2-10% of white blood cells (200-800 /cmm on a full blood count) they are produced in the bone marrow and travel in the bloodstream to their target tissues, where they become macrophages they have roles in phagocytosis, antigen presentation and cytokine production they are large cells with fine “ground-glass” granules and horseshoe-shaped nuclei We mentioned Cytokines before as the chemical signals which attract immune cells to the infection site. Cytokines also can be secreted by inflammed epithelial cells  B- TISSUE MACROPHAGES These are tissue cells and therefore aren’t found on a full blood count They are derived from blood monocytes, which differentiate once they reach their target tissues into macrophages. There are many types of macrophage which are specifically adapted to different tissues – these include Küpffer cells in the liver, alveolar macrophages in the lungs, osteoclasts in bone and microglial cells in neurons  they clear any pathogens, foreign debris and old or dead cells from their tissues by phagocytosis  they also perform antigen presentation and can activate memory cells  Secrete cytokine NB Phagocytosis: They have processes on their cell membranes called pseudopodia which extend around the target particle. once internalized, the phagosome is fused with another vesicle called a lysosome containing either reactive oxygen species or enzymes, which break down its contents NB like monocytes, they are large cells with horseshoe-shaped nuclei  LYMPHOCYTES (AGRANULOCYTES) (Small, specialised white blood cells with large nuclei and no granules) Normally make up 20-45% of all white blood cells (1300-3500 /cmm on a full blood count) There are three main subtypes of lymphocytes: B cells, T cells and natural killer (NK) cells  B cells and T cells make up the majority of the lymphocyte population. They are small cells with large round nuclei, scanty bluish cytoplasm and no granules, The only way to differentiate them apart is by using a special staining for specific cell surface markers known as clusters of differentiation (CDs).’ B & T cells : mainly involved in adaptive immunity Natural killers ( NK ) :are involved in both; the innate & adaptive immunity NK cells are a larger, more primitive lymphocyte subtype which does contain some granules.  A- B CELLS B cells represent about 10-15% of the total lymphocyte population – important B cell surface markers include CD19, CD20 and CD21, as well as MHC II (that is why they have a role in antigen processing and presentation) Essential for humoral immunity, also known as the antibody-mediated immune response  the plasma cells are mature B cells which secrete antibodies,  memory B cells “remember” the offending foreign antigens to allow the immune system to mount a quicker antibody response to any subsequent infections  B- T CELLS T cells represent about 75% of the total lymphocyte population - this varies depending on the activity of the immune response. all T cells express CD3 on their surfaces, along with T cell receptors (TCRs) which recognize specific antigens presented in an MHC I or MHC II molecule by the antigen presenting cells  T cell subtypes 1- helper T cells (CD4) facilitate the activation of the immune response and stimulate division and differentiation of various effector cells 2- cytotoxic T cells (CD8) provide cell-mediated immunity by targeting and killing viral infected cells (and tumor cells) 3-regulatory T cells (CD25 + FOXP3) – also known as suppressor T cells – play a vital role in limiting the immune response to prevent excessive damage to tissues and organs 4-memory T cells (CD62 + CCR7) “remember ” what has happened to allow the immune system to mount a faster, more effective response should the offending organism be foolish enough to return Doctor said these are the most important ones : UNMETURE T CELL CD3 T HELPER CD4 CTYOTOXIC T CELL CD8  C-NATURAL KILLER CELLS NK cells represent about 5% of the total lymphocyte population – again, this varies depending on what ’s going regarding the immune response. They are a larger lymphocyte subtype with granules in their cytoplasm – they are also known as large granular lymphocytes (LGLs) Scientists used to call it in “Non-B Non-T cells” They express CD16 and CD56. NK cells actually form part of both the innate and adaptive immune systems and are able to destroy pathogens and infected cells without the need for specific antigen recognition (No MHC restriction). They are also particularly important in immunity against viral infections and tumors.  The normal immune response can be broken down into four main components: Pathogen recognition by cells of the innate immune system, with cytokine release, complement activation and phagocytosis of antigens  The innate immune system triggers an acute inflammatory response to contain the infection  Meanwhile, antigen presentation takes place with activation of specific T helper cells  humoral immunity from B cells and antibodies, and cell-mediated immunity from cytotoxic CD8 T cell.  Innate immuntiy Specific immnit Aquired immunity Immediately after infection Relatively delayed This is the first line of defense (require full recognition for organism). It is very fast – it is established within about 4 hours Less efficient More efficient Non specific Specific include Include: B lymphocyte 1- Mechanical Barrier : and secretion And T lymphocyte 2- a chemical response 3- Cell : Neutrophil, esinophil, basophil, monocyte, macrophage , NK 4-inflammatory response. No memory Memory present  Mechanisms of Innate Immunity I. Mechanical barriers and surface secretions and flora II. Chemical response III. Cellular defense mechanisms IV. Inflammation INNATE II 1- INNATE CELLULAR IMMUNE RESPONSE Questions: 1-mention one of the phagocytes cell 2- mention the most important cell 1- Phagocytes blood monocytes, tissue macrophages dendritic cells and, most importantly, neutrophils: (only appear in response to infection or injury, and are therefore not found in a healthy tissue. ) Some of them will be stored in secondary lymphoid organs: which lymph node and spleen. until any sort of injury or infection apper.  The innate immune system recognizes structures that are shared by various classes of microbes and are not present on normal host cells. Each component of innate immunity may recognize many bacteria, viruses, or fungi. For example, phagocytes express receptors for bacterial endotoxin, also called lipopolysaccharide (LPS), and other receptors for peptidoglycans, each of which is present in the outer membranes or cell walls of many bacterial species but is not produced by mammalian cells. The receptors of the innate immune system are encoded by inherited genes that are identical in all cells. The pattern recognition receptors of the innate immune system are nonclonally distributed; that is, identical receptors are expressed on all the cells of a particular type, such as macrophages. Therefore, many cells of innate immunity may recognize and respond to the same microbe. This is in contrast to the antigen receptors of the adaptive immune system, which are encoded by genes formed by rearrangement of gene segments during lymphocyte development, resulting in many clones of B and T lymphocytes, each expressing a unique receptor.  All receptors(phagocytes have so many of tool like receptor) on phagocytes are the same for recognizing different pathogens. they recognize PAMP on the pathogene Phagocytes identify pathogens by recognizing pathogen-associated molecular patterns (PAMPs) using pathogen recognition receptors (PRRs):Toll like receptor Are there phagocytes in the adaptive immune system? A: No, but phagocytes will be increased in efficiency by cytokines.  Damage-associated molecular patterns (DAMPs). Like, necrotic cell will also be recognize by phagocytes. Damage-associated molecular patterns (DAMPs). Like, necrotic cell will also be recognize by phagocytes.  The NOD-like receptors (NLRs) are a large family of innate receptors that sense DAMPs and PAMPs in the cytosol of cells and initiate signaling events that promote inflammation. simmilar to Tool like receptor, but they are presenting inside the cell ( in the cytosol)  After identification: A- Internalize them, kill them and digest them B- present the digested protein antigens to the cells of the adaptive immune system via major histocompatibility complexes (MHCs) T cells can only react to an antigen if it is presented within an MHC complex. This phenomenon is known as MHC restriction..  MHC It is another surface molecule present only on phagocytec cells and all somatic cells , there are different types of MHCs ( type 1 and type 2 ) , type 1 present in all nucleated cells even somatic cells, since they have a nucleus contain MHCs type 1 , type 2 present only as a surface molecule on the antigen presenting cells so the antigen presenting cells ( like B cell and macrophage ) on the surface Both component ( type 1 and type 2 ) type 1 as nucleotide cell and type 2 becase it is an antigen presenting cells  C- a transcription factor is activated which results in the release of proinflammatory cytokines and the initiation of the inflammatory response  The Mechanism of Phagocytosis: Four main phases: The order of events is important, question will be asked chemotaxis,adherence, ingestion, digestion 1- Chemotaxis is the chemical attraction of phagocytes to microorganisms. chemotactic chemicals : microbial products, damaged tissue cells, cytokines released by other white blood cells, and peptides derived from complement system. 2- Adherence is the attachment of the phagocyte’s plasma membrane to the surface of the microorganism or other foreign material facilitated by the attachment of pathogen- associated molecular patterns (PAMPs) of microbes to receptors, such as Toll-like receptors (TLRs), on the surface of phagocytes. There are different type of tool like receptors “ not mentioned”  Opsonization; facilitated or enhanced Microorganisms can be more readily phagocytized if they are first coated with certain serum proteins that promote attachment of the microorganisms to the phagocyte. This coating process is called opsonization. The proteins that act as opsonins include some components of the complement system and antibody molecules. Very improtant Enhanced phagocytosis: when pathogens escape is Opsonization innate or acquired? phagocytosis by tool like receptor, the microphage will act complement system -> Opsonization innate as antigen presenting cell amplifying the adaptive immunity and it will produce antibodies. So, it will be Antibody molecules -> Opsonization Aquired engulfed along with antibodies. The process is not named phagocytosis it is named Opsonization. The name depends on which receptor is used in the process. Opsonization and phagocytosis. C3b coats microbes and promotes the binding of these microbes to phagocytes by virtue of receptors for C3b that are expressed on the phagocytes. Thus, microbes that are coated with complement proteins are rapidly ingested and destroyed by phagocytes. This process of coating a microbe with molecules that are recognized by receptors on phagocytes is called opsonization.  3- Ingestion During this process, the plasma membrane of the phagocyte extends projections called pseudopods surrounding the microorganism with a sac called a phagosome, or phagocytic vesicle The membrane of a phagosome has enzymes that pump protons (H+) into the phagosome, reducing the pH to about 4. At this pH, hydrolytic enzymes are activated 4- Digestion In this phase of phagocytosis, the phagosome pinches off from the plasma membrane and enters the cytoplasm It contacts lysosomes that contain digestive enzymes and bactericidal substances. substances destroying bacteria On contact, the phagosome and lysosome membranes fuse to form a single, larger structure called a phagolysosome  Lysosomal enzymes 1-lysozyme, which hydrolyzes peptidoglycan in bacterial cell walls. 2- lipases, proteases, ribonuclease, and deoxyribonuclease, hydrolyze other macromolecular components of microorganisms 3- also contain enzymes that can produce toxic oxygen products such as superoxide radical (O2–), hydrogen peroxide (H2O2), nitric oxide (NO), Important singlet oxygen (1O2−), and hydroxyl radical (OH·) Mechanism of.(Toxic oxygen products are produced by a intracellular killing by the phagocyte cells is called oxidative burst This process needs process called an oxidative burst) oxygen  This process DON’T oxygen enzyme myeloperoxidase converts chloride (Cl−) ions and hydrogen peroxide into highly toxic hypochlorous acid (HOCl). The acid contains hypochlorous ions, which are found in household bleach and account for its antimicrobial activity.  After enzymes have digested the phagolysosome contains indigestible material and is called a residual body. This residual body then moves toward the cell boundary and discharges its wastes outside the cell  Natural killer cells (NK cells)  Unlike T cells, they do not require activation by specific antigens, which means they are able to respond immediately when exposed to a pathogen  “Self” cells are protected from the destructive action of NK cells by the inhibitory effects of MHC I, which is expressed on the surface of all nucleated body cells  Normally, NK cells cannot attack healthy “self” cells. However, MHC I expression is often suppressed if cells are infected with viruses, or have become cancerous. NK cells can, therefore, perform additional vital roles in viral immunity and tumor rejection. Improtant  NK cells do this by releasing toxic granules to induce apoptosis  You can see that the ligand always interact with the receptor. So , how can NK cell do not kill normal body cell? by Presenting MHC 1 on the cell, this will inhibit the process. of there is no MHC 1 on the cell NK cell will secrete toxins granules that will initiate apoptosis. MHC 1 won’t be presenting in some cases, malignant transformation, vairal infection. Therefore the Abnormal cell will be recognize by NK cell  2-Inflammatory Response The acute inflammatory response (innate immune cells, proinflammatory cytokines and complement proteins). to localize and contain the infection in the period of hours after its onset, (when the innate immune system is running out of stream and the specific cellular immune response is still trying to get going.) The main features of this process are: 1- Vasodilation and increased blood flow – this leads to erythema and warmth 2- Increased vascular permeability – this allows an inflammatory cell infiltrate to extravasate and reach the site of infection, and also causes tissue oedema and swelling 3- Release of inflammatory mediators such as bradykinins and prostaglandins which increase pain sensitivity in the infected area 4-Microvascular coagulation – this is induced by local tissue damage, and acts to confine the infection and prevent its spread.  In histology, Ferritin is the storage of iron in the body  Neutrophil chemotaxis – neutrophils migrate to the site of infection and begin their clean-up operation, phagocytosing pathogens and debris.  Systemic features such as fever and raised inflammatory markers such as C-reactive Improtant protein (CRP) and ferritin – this produces unpleasant “flu-like” symptoms such as hot flushes, sweats, chills, rigors, headache, nausea, myalgia, arthralgia and fatigue Upregulation of costimulatory molecules such as MHC-II and B7 to encourage activation of the adaptive immune system. More details in Acquired immunity lecture  MHC : Major histocompatability complex MHC I : All nucleated cell Macrophage , B cell Have MHC II : Macrophage , B cell both MHC 1 MHC 2.  Vesicular antigen Cytosolic Antigen ( viral) (Macrohage) presented presented on MHC I on MHC II to to T Hepler cell (CD4) T cytotoxic (CD8)  team Wishes you the best