Blood Physiology-II; Immunity, Infection, and Inflammation (2024) PDF

Blood Physiology; Immunity, Infection, & Inflammation  Immunity Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells  Immunity consists of following activities: – Defense against invading pathoge...

Blood Physiology; Immunity, Infection, & Inflammation  Immunity Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells  Immunity consists of following activities: – Defense against invading pathogens (viruses & bacteria) – Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g., from injury or disease) – Identification & destruction of abnormal or mutant cells (primary defense against cancer) – Rejection of 'foreign' cells (e.g., organ transplant) – Inappropriate responses: Allergies - response to normally harmless substances Autoimmune diseases  The immune system A functional system – NOT an organ system: Complex system – includes Skin – physical barrier Lining of mucus membranes – physical barrier Secretions – tears, mucus etc - antimicrobial Blood cells and vasculature – WBCs Bone marrow Liver – makes complement proteins Most tissues – have resident immune cells Lymphatic system and lymphoid organs  The lymphatic system is part of the circulatory system and a vital part of the immune system. The lymphatic system consists of a conducting network of lymphatic vessels, lymphoid organs, lymphoid tissues, and the circulating lymph. Lymphatic vessels carry a clear fluid called lymph directionally towards the heart. Unlike the cardiovascular system, the lymphatic system is not a closed system.  lymphoid organs The primary (or central) lymphoid organs generate lymphocytes from immature progenitor cells. The thymus and the bone marrow constitute the primary lymphoid organs. The secondary (or peripheral) lymphoid organs, which include lymph nodes and the spleen, – They maintain mature lymphocytes and initiate an adaptive immune response.  The relationship cardiovascular system and lymphatic system The heart pumps 5 liters of blood per minute, 300 liters per hour and 7200 liters per day. An average of 20 litres of blood plasma pass to interstitial space through capillary filtration per day. Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the The remaining plasma is drained by the remaining 3 litres remain in closed ended lymphatic vessel. the interstitial fluid. One of the main functions of the lymphatic system is to provide an accessory return route to the blood for the surplus three litres.  Lymphatic system The other main function of lymphatic system is related to the immune system. Lymph is very similar to blood plasma: it contains lymphocytes and other white blood cells but not red blood cells. It also contains waste products and debris of cells together with bacteria and protein. –Debris is organic waste from dead or damaged tissue Organs such as the thymus gland and lymph nodes that make up the lymphoid tissue are the production and maturation sites of some lymphocytes.  The immune system A functional system – NOT an organ system: Complex system – includes Skin – physical barrier Lining of mucus membranes – physical barrier Secretions – tears, mucus etc - antimicrobial Blood cells and vasculature – WBCs Bone marrow Liver – makes complement proteins Most tissues – have resident immune cells Lymphatic system and lymphoid organs  Cellular Elements of Blood 1. Red Blood Cells 2. White Blood Cells 3. Platelets phagocytosis  IMMUNE EFFECTOR CELLS granulocytes and agranulocytes The circulating immune cells include granulocytes (polymorphonuclear leukocytes, PMNs), comprising neutrophils, eosinophils, and basophils And agranulocytes comprising lymphocytes; and monocytes. Immune responses in tissues are further enhanced by these cells as well as tissue macrophages and mast cells. Macrophages are derived from circulating monocytes and mast cells are related to circulating basophils.  IMMUNE EFFECTOR CELLS granulocytes and agranulocytes neutrophils, eosinophils, basophils Lymphocytes Monocytes + tissue macrophages mast cells.  GRANULOCYTES All granulocytes have cytoplasmic granules that contain biologically active substances involved in inflammatory and allergic reactions. The average half-life of a neutrophil in the circulation is 6 h. It is necessary to produce more than 100 billion neutrophils per day to maintain normal circulating blood levels. Many neutrophils enter tissues, especially in the event of infection or inflammation.  GRANULOCYTES -NEUTROPHILS 50-70% of all leukocytes (most abundant of WBC’s) are neutrophils Important in inflammatory responses. Most important cells of the innate immune system They are phagocytes that engulf bacteria and debris  Neutrophils and Inflammatory response- chemotaxis Invasion of the body by bacteria triggers the inflammatory response. The bone marrow is stimulated to produce and release large numbers of neutrophils. Bacterial products interact with plasma factors and cells to produce agents that attract neutrophils to the infected area (chemotaxis). The chemotactic agents, which are part of a large and expanding family of chemokines, include a component of the complement system (C5a); leukotrienes; and polypeptides from lymphocytes, mast cells, and basophils.  Neutrophils and Inflammatory response- opsonization Plasma factors act on the bacteria to make them “tasty” to the phagocytes (opsonization). The principal opsonins are immunoglobulins of a particular class (IgG) and complement proteins. – They coat the bacteria  GRANULOCYTES -EOSINOPHILS * 1-4% of the WBC's * Attack parasitic worms * Important in allergic reactions GRANULOCYTES -EOSINOPHILS Eosinophils have some selectivity in the way in which they respond and in the killing molecules they secrete. They are especially abundant in the mucosa of the gastrointestinal tract, where they defend against parasites, and in the mucosa of the respiratory and urinary tracts. Circulating eosinophils are increased in allergic diseases such as asthma and in various other respiratory and gastrointestinal diseases. GRANULOCYTES -BASOPHILS * 0.5% of the WBC's * Release histamine and heparin * Important in Allergic Reactions * Heparin helps clear fat from blood  Basophils Basophils also enter tissues and release histamine and other inflammatory mediators when activated They participate in immediate-type hypersensitivity (allergic) reactions.  Allergic reactions range from mild urticaria and rhinitis to Basophils severe anaphylactic shock. – Urticaria, also known as hives, is an outbreak of swollen, pale red bumps or plaques (wheals) that suddenly appear on the skin. – Hives occur as a result of the body's response to certain allergens or for unknown reasons. – Hives often cause itching, but can also cause burning or stinging.  Rhinitis is inflammation Basophils and swelling of the mucous membrane of the nose, It is characterized by a runny nose and stuffiness and usually caused by the common cold or a seasonal allergy.  MAST CELLS Mast cells are heavily granulated cells of the connective tissue. They are involved in inflammatory responses initiated by immunoglobulins IgE and IgG. Anaphylaxis is a serious, life- Marked mast cell threatening allergic reaction. activation produces The common anaphylactic clinical manifestations of reactions are to foods, insect allergy up to and including stings, medications and latex anaphylaxis.  Types of WBC’s Agranulocytes Granulocytes Each WBC has a specific function  AGRANULOCYTES-MONOCYTES 2-6 % of the WBC's Monocytes enter the blood from the bone marrow and circulate for about 72 h. Monocytes then enter the tissues and become tissue macrophages. They play a key role in innate immunity.  tissue macrophages The tissue macrophages include the Kupffer cells of the liver, pulmonary alveolar macrophages, microglia in the brain, osteoclasts in the bone All of them come originally from the circulation.  AGRANULOCYTES-LYMPHOCYTES 25-33 % of the WBC’s Lymphocytes are key elements in the production of acquired immunity. After birth, some lymphocytes are formed in the bone marrow. Bone marrow constantly produces cells that will become lymphocytes. However, most are formed in the lymph nodes, thymus, and spleen from precursor cells. Precursor cells originally came from the bone marrow. Cells processed in the thymus become T cells. Cells processed in bone marrow become B cells.  LYMPHOCYTES 25-33 % of the WBC’s About 25 percent of the new lymphocytes remain in the bone marrow and become B lymphocytes (B cells). The other 75 percent travel to thymus gland and become T lymphocytes (T cells) Lymphocytes enter the bloodstream for the most part via the lymphatics. At any given time, only about 2% of the body lymphocytes are in the peripheral blood. Most of the rest are in the lymphoid organs. LYMPHOCYTES  LYMPHOCYTES 25-33 % of the WBC’s T cells are involved in cell- mediated immunity, whereas B cells are primarily responsible for humoral immunity (relating to antibodies). B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects T-lymphocytes directly also like bacteria and viruses. destroy virus-invaded cells and cancer cells.  Leukocytosis Leukocytosis is the number of white cells (leukocytes) in the blood above the normal range. – Normal value is 4.000- 11.000 per/mm3 It is frequently a sign of an inflammatory response, most commonly the result of infection,  Leukocytosis but may also occur following certain parasitic infections or bone tumors as well as leukemia. It may also occur after strenuous exercise, convulsions such as epilepsy, emotional stress, pregnancy and labor, anesthesia, and epinephrine administration.  Leukocytosis There are five types of leukocytosis: – Neutrophilia (the most common form) – Lymphocytosis – Monocytosis – Eosinophilia – Basophilia  Leukemia-abnormal increase in BC Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. Cancer cells may differentiate into mature cells or not show sufficient differentiation. In acute leukemias, cells are less differentiated. In chronic leukemia, myeloid and lymphoid cells can differentiate into mature cells, but their functions are insufficient. Since the functions of differentiated myeloid and lymphoid cells are insufficient, they cannot provide sufficient protection against infections. Since normal bone marrow is replaced by dysfunctional leukemic cells in leukemia, bleeding due to infection, anemia and thrombocytopenia may develop.  Leucopenia Leukopenia is a decrease in the number of white blood cells(leukocytes) found in the blood, which places individuals at increased risk of infection. Decreased white blood cell are usually the neutrophil. – In this case the decrease may be called neutropenia. Less commonly, a decrease in lymphocytes (called lymphocytopenia) may be seen.  Immunity Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells Overview of the Immune System Immune System Innate Acquired (Nonspecific) (Specific) 1o line of defense 2o line of defense Interactions between the two systems  A typical immune response INNATE IMMUNITY ACQUIRED IMMUNITY Rapid responses to a Slower responses to broad range of microbes specific microbes External defenses Internal defenses Skin Phagocytic cells Humoral response Mucous membranes Antimicrobial proteins (antibodies) Secretions Inflammatory response Invading microbes Natural killer cells Cell-mediated response (pathogens) Complement (cytotoxic lymphocytes) Innate immunity vs Acquired Immunity Innate Immunity Acquired Immunity (first line of defense) (second line of defense) No time lag A lag period Not antigen specific Antigen specific No memory Development of memory  The innate immune System Innate Immune System External Internal defenses defenses Innate immune system has external and internal defense mechanisms.  Anatomical Barriers - Mechanical Factors Some mechanisms provide mechanical protection against foreign invading Skin microorganisms on surfaces in the body that are in contact with the external environment. Mucociliary escalator Flushing action of saliva, tears, urine Anatomical Barriers – Chemical factors Some chemical substances found on these anatomical surfaces help this protection. Antimicrobial HCl in stomach Lysozyme in tears /saliva Peptides in sweat  Anatomical Barriers – Biological factors Some biological factors also found on these anatomical surfaces help this protection Normal flora – microbes in many parts of the body Normal flora – > 1000 species of bacteria Normal flora – competes with pathogens for nutrients and space  internal defences of Innate immune system include blood cells and other blood components. Neutrophils Monocytes /macrophages NK cells Innate immune system: components of Blood Complement proteins Coagulation proteins Cytokines WBCs  Cytokines Small proteins – secreted by cells of the immune system Affect the behaviour of other cells signalling molecules Key players in innate and acquired immunity  Which cells release cytokines ? Cells of the immune system: Neutrophils – when they encounter a pathogen Macrophages – when they encounter a pathogen NK cells – on encountering a microbe infected cell /tumour cell Lymphocytes – when they are activated  Examples of cytokines Interferons Interleukins Tumour necrosis factor (TNF)  Interferons (IFN) Signalling proteins produced by virus infected monocytes and lymphocytes Secreted proteins – Key anti-viral proteins “Interfere” with virus replication Warn the neighbouring cells that a virus is around... Prewarned cells are able to quickly inhibit the virus If we did not have IFNs – most of us may die of influenza virus infection  Interleukins Interleukins (ILs) are a group of cytokines that were first seen to be expressed by leukocytes. The human genome encodes more than 50 interleukins and related proteins. 36 of them have been identified – ILss1 – ILs36 Not stored inside cells Quickly synthesized and secreted in response to infection Key modulators of behaviour of immune cells Mostly secreted by T-lymphocytes & macrophages. They promote the development and differentiation of T and B lymphocytes, and hematopoietic cells.  Complement proteins or system(C`) A large number of distinct plasma proteins that react with one another (C1 thro’ C9) Complement can bind to microbes and coat the microbes Essential part of innate immune response Enhances adaptive immune response Overview of the Immune System Immune System Innate Acquired (Nonspecific) (Specific) 1o line of defense 2o line of defense Interactions between the two systems  ACQUIRED IMMUNITY The key to acquired immunity is the ability of lymphocytes to produce antibodies (in the case of B cells) or cell surface receptors (in the case of T cells) specific to one of the millions of foreign substances that can invade the body. Acquired immunity has two components: – humoral immunity and – cellular immunity.  Humoral immunity Humoral immunity is mediated by circulating immunoglobulin antibodies in the γ-globulin fraction of the plasma proteins. Immunoglobulins are produced by differentiated forms of B lymphocytes. They activate the complement system and attack and neutralize antigens. Humoral immunity is a major defense against bacterial infections.  Cellular immunity Cellular immunity is mediated by T lymphocytes. It is responsible for delayed allergic reactions and rejection of transplants of foreign tissue. Cytotoxic T cells attack and destroy cells bearing the antigen that activated them. Cellular immunity constitutes a major defense against infections due to viruses, fungi, and a few bacteria such as the tubercle bacillus. It also helps defend against tumors.  Inflammation Inflammation is a complex localized response to foreign substances such as bacteria or in some instances to internally produced substances. It includes a sequence of reactions initially involving cytokines, neutrophils, adhesion molecules, complement, and IgG. Later, monocytes and lymphocytes are involved. Arterioles in the inflamed area dilate, and capillary permeability is increased So It is associated with swelling of tissue Inflammation is key event in innate immune response.  All roads lead to inflammation Neutrophils Coagulation proteins Monocytes /macrophages Inflammation C` proteins NK cells Cytokines /IFN TLRs Cellular Extracellular  Inflammation and vascular changes Vasodilatation Increased capillary permeability Normal blood vessel Normal blood vessel Dilated blood vessel Leaky blood vessel  Signs of inflammation Vascular changes Capillary Vasodilatation permeability Heat / redness Swelling Pain Temporary Fever loss of function  Inflammation and innate immunity Histamine Pathogen removal +++ Adaptive immune response Mast cells – similar to basophils in blood; mast cells are present in tissues and release histamines in response to wound / infection /irritant Signs of inflammation  Role of Inflammation in innate immunity Initiation of phagocytosis – killing of pathogen Limiting the spread of infection Stimulate adaptive immune response Initiate tissue repair The good and bad about inflammation Acute /short-term -Good chronic /long-term - Bad Chronic inflammation = tissue damage Normal tissue Chronic inflammation - macrophages in the injured tissue. Macrophages release toxins (including reactive oxygen species or ROS) that injure Tissue : chronic inflammation tissues chronic inflammation is almost always accompanied by tissue destruction.  Inflammation Chronic Inflammation is a key component of asthma, ulcerative colitis, Crohn disease, rheumatoid arthritis, and many other diseases.  SYSTEMIC RESPONSE TO INFLAMMATION AND INJURY Some systemic responses are also produced during inflammation and also as a response to injuries. These include alterations in plasma acute phase proteins, Many of the proteins are of liver origin. Thus, for example, an increase in C-reactive protein (CRP) activates monocytes and causes further production of cytokines.  WOUND HEALING When tissue is damaged, platelets bind to collagen and laminin. Blood coagulation produces thrombin, which promotes platelet aggregation and granule release. The platelet granules generate an inflammatory response.  WOUND HEALING Cytokines released by the white blood cells and platelets stimulate fibroblasts and epithelial cells. Fibroblasts and epithelial cells mediate wound healing and scar formation. Fibroblasts produce collagen fibers. Collagen synthesis is upregulated, producing the scar-wound tissue. Wounds gain 20% of their ultimate strength in 3 weeks and later gain more strength, but they never reach more than about 70% of the strength of normal skin. Autoimmunity -Autoimmune diseases Sometimes the processes that eliminate antibodies against self-antigens fail and a variety of different autoimmune diseases are produced. These can be B cell- or T cell-mediated and can be organ-specific or systemic. They include – type 1 diabetes mellitus (antibodies against pancreatic islet B cells), – myasthenia gravis (antibodies against nicotinic cholinergic Acetylcholine receptors), and – multiple sclerosis (antibodies against myelin sheat). In some instances, the antibodies are against receptors and are capable of activating those receptors; – for example, antibodies against TSH receptors increase thyroid activity and cause Graves disease.  THERAPEUTIC HIGHLIGHTS OF AUTOIMMUNITY The therapy of autoimmune disorders include on efforts – to replace or restore the damaged function (eg, provision of exogenous insulin in type 1 diabetes) – as well as nonspecific efforts to reduce inflammation (using corticosteroids) – or to suppress immunity.  VACCINATION-ACTIVE IMMUNITY Our body’s resistance improve when it encounters microorganisms and their toxins or other antigenic components. This improvement is known as active immunity. In other words, the antibody or T cell activation in response to the foreign agent are active immunity. In order to develop active immunity, individuals can be vaccinated with dead microorganisms carrying antigens, weakened live microorganisms or toxins. The basic principle in vaccination is to stimulate the acquired immune system of the person to fight diseases. Memory cells form the basis of immunization by vaccination. VACCINATION-PASSIVE IMMUNITY Temporary or passive immunity can be created without applying antigen in individuals. This situation known as passive immunity. It is achieved by applying antibodies and active T cells separately or in combination, taken from another person or animal, for whom active immunity to the antigen has been formed. – Antibody therapy  ACTIVE VS PASSIVE IMMUNITY Active immunity provides long protection as it creates immunological memory, while passive immunity provides temporary protection for a few days since antibodies and T cells are applied.