Complement System PDF

Complement System The complement system is part of the immune system that defends our body against injury and foreign invaders like bacteria and viruses. The complement system is made up of about 50 distinct plasma proteins that react with one another to opsonize pathogens and induce a series of i...

Complement System The complement system is part of the immune system that defends our body against injury and foreign invaders like bacteria and viruses. The complement system is made up of about 50 distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection. Note: opsonization is an immune process which uses opsonins to tag foreign pathogens for elimination by phagocytes by making the pathogens more susceptible to phagocytosis. Note: opsonins are antibody or other substance which binds to foreign microorganisms or cells making them more susceptible to phagocytosis.  The proteins that make up the complement system are inactive or turned off until a trigger turns them on. Triggers could include an injury to our body or bacteria that enter our body.  One protein will turn on, which activates the next protein in line to turn on. This chain reaction is called a cascade. A number of complement proteins are proteases that are themselves activated by proteolytic cleavage. Such enzymes are called zymogens The complement system activates through a triggered- enzyme cascade. In such a cascade, an active complement enzyme generated by cleavage of its zymogen precursor then cleaves its substrate, another complement zymogen, to its active enzymatic form. This in turn cleaves and activates the next zymogen in the complement pathway. The bulk of the complement proteins that are present in serum are produced and secreted by the hepatocytes in the liver, and circulate throughout the blood and tissues. There are three ways in which the complement system protects against infection: a. First, it generates large numbers of activated complement proteins that bind covalently to pathogens, opsonizing them for engulfment by phagocytes bearing receptors for complement. b. Second, the small fragments of some complement proteins act as chemo-attractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. c. Third, the terminal complement components damage certain bacteria by creating pores in the bacterial membrane. There are three pathways of complement activation: i. The classical pathway, which is triggered by antibody or by direct binding of complement component C1q, the first protein in the complement cascade, directly to the pathogen surface. It can also be activated during an adaptive immune response by the binding of C1q to antibody:antigen complexes, and is thus a key link between the effector mechanisms of innate and adaptive immunity. ii. The mannose-binding lectin pathway (MB-lectin pathway) is initiated by binding of the mannan-binding lectin, a serum protein, to mannose-containing carbohydrates on bacteria or viruses. iii.Finally, the alternative pathway can be initiated when a spontaneously activated complement component binds to the surface of a pathogen. Each pathway follows a sequence of reactions to generate a protease called a C3 convertase. These reactions are known as the ‘early’ events of complement activation, and consist of triggered-enzyme cascades in which inactive complement zymogens are successively cleaved to yield two fragments, the larger of which is an active serine protease. The C3 convertases formed by these early events of complement activation are bound covalently to the pathogen surface. Here they cleave C3 to generate large amounts of C3b, the main effector molecule of the complement system, and C3a, a peptide mediator of inflammation. C3b also binds the C3 convertase to form a C5 convertase that produces the most important small peptide mediator of inflammation, C5a, as well as a large active fragment, C5b, that initiates the ‘late’ events of complement activation. These comprise a sequence of polymerization reactions in which the terminal complement components interact to form a membrane-attack complex (MAC), which creates a pore in the cell membranes of some pathogens that can lead to their death. What are common conditions that affect the complement system? The complement system is an important part of the immune system and functions to prevent infection and illness. If the complement proteins aren’t working as expected, or if one doesn’t have enough of them (complement deficiency), one is considered immunocompromised and the body is at risk of infections that can be very serious (sepsis). If the complement proteins are working too hard and activating too frequently, one may be at risk for several autoimmune or inflammatory conditions. Common conditions that the complement system can be involved in include:  Allergic asthma.  Anemia.  Cancer (leukemia, lymphoma).  Kidney disease.  Macular degeneration.  Rheumatoid arthritis. Common signs or symptoms of complement system conditions? If the complement system isn’t functioning properly, the immune system will be weaker than it should be. Symptoms of complement system conditions include:  Frequent infections.  Fatigue and feeling tired.  Joint pain.  Swelling (inflammation). The complement pathway leading to such potent inflammatory and destructive effects, and which, moreover, has a series of built-in amplification steps, is potentially dangerous and must be subject to tight regulation. One important safeguard is that key activated complement components are rapidly inactivated unless they bind to the pathogen surface on which their activation was initiated. There are also several points in the pathway at which regulatory proteins act on complement components to prevent the inadvertent activation of complement on host cell surfaces, hence protecting them from accidental damage.  Cytokines: The immune system is a network with several parts that work together to protect the body from threats, it contains immune cells that fight invading pathogens, allergens and other harmful substances. Cytokines signal those immune cells to fight the invaders. Cytokines are small proteins that are important in cell signaling, controlling the growth and activity of other immune system cells and blood cells. When released, they signal the immune system to do its job. Cytokines affect the growth of all blood cells and other cells that help the body's immune and inflammation responses.  Cytokines are made by many cell populations, but the predominant producers are helper T cells (Th) and macrophages. Cytokines may be produced in and by peripheral nerve tissue during physiological and pathological processes by resident and recruited immune cells including:  Macrophages.  Dendritic cells.  Lymphocytes (T and B lymphocytes).  Monocytes.  Neutrophils.  Basophils.  Eosinophils.  Mast cells. Other cells that aren’t considered immune cells that also release cytokines include:  Endothelial cells (cells that line the inside of the blood vessels).  Epithelial cells (cells that line the organs).  Fibroblasts (cells in connective tissue).  Stromal cells (cells in connective tissue).  Schwann cells (cells that surround neurons).  Various cells can release the same kind of cytokine. Some cytokines stimulate the immune system and others slow it down. Too many cytokines can lead to excess inflammation and conditions like autoimmune diseases  Classification of Cytokines Cytokines are subdivided based on the nature of the immune response and the source of their production. They include: Lymphokines---cytokines made by lymphocytes Monokines-----cytokines made by monocytes Chemokines----cytokines with chemotactic activities, chemokines direct immune cells toward places in the body where they can fight  Interleukins---- cytokines made by one leukocyte/other cells and acting on other leukocytes/cells  Interferons----- interferons signal cells to put up their defenses against viruses invading the body. Interferons “interfere” in the process that allows viruses to replicate, or make more viruses once they’ve invaded a healthy cell  Tumor necrosis factors---- TNF-helps regulate inflammation in the body. TNF also signals to immune cells that kill tumor cells  Colony-stimulating factors---- CSF- signals hematopoietic stem cells to develop into specific cell types  Functions of cytokines  Cytokines are released when there’s a threat in the body.  Cytokines are most known for regulating inflammation in the body.  Inflammation is a sign that the body’s immune cells are fighting invaders or healing tissue damage.  The cytokines tell the immune cells how to fight i. Cell activation: Cytokines tell cells where to go and what to do. For example, cytokines can direct immune cells toward an infection site so the cells can fight germs there. They can heighten or lessen the processes associated with inflammation. ii. Cell differentiation: Cytokines can tell immature cells to develop into a specific type of cell. For example, cytokines can tell an immature cell to mature into a white blood cell capable of fighting infection. iii. Cell proliferation: Cytokines can tell a cell to make more cells just like it. For example, cytokines can tell a white blood cell to make more white blood cells to fight infection. iv. Cytokines can also signal the body’s cells to release more cytokines to increase the body’s inflammatory response.  pro-inflammatory and anti-inflammatory cytokines  Pro-inflammatory cytokines trigger or heighten inflammation. They relay messages that coordinate the body’s immune response to fend off attackers, like germs.  Anti-inflammatory cytokines stop or lessen inflammation. They relay messages that prevent an excessive immune response that can lead to tissue damage.  Stopping the body’s inflammatory response is just  Mechanisms of cytokines function  Certain cells release cytokines while other cells contain cytokine receptors. When the cytokine (key) enters the cytokine receptor (lock), the receiving cell receives a message that tells it what to do. The cell acts based on the message it receives. a.Autocrine signaling: Cytokines can bind to receptors on the same cell that released it. b.Paracrine signaling: Cytokines can bind to receptors on nearby cells. c.Endocrine signaling: Cytokines can bind to receptors on cells located far away from the cell that released the cytokines. Diseases or conditions that involve cytokines Cytokines are so essential to the immune system that they play a role in most conditions and diseases. If the immune system releases too many cytokines in response to an infection or treatments like immunotherapy it may develop cytokine release syndrome (CRS), also called a cytokine storm. This results in various symptoms that affect multiple body systems. CRS can be life-threatening without treatment. i. Autoimmune diseases ii.Metabolic disorders iii.Cancer. iv.Sepsis  Cytokine panel A cytokine panel is a blood test that checks the cytokine levels to determine if the body is producing too many or too few cytokines. Elevated cytokines may be a sign of heightened inflammation, and may need medication to help.  Inflammation Inflammation is part of the biological (body’s) response to injuries, irritants, illness and invaders (like pathogens). Five basic signs associated to inflammation are heat, pain, redness, swelling, and loss of function Inflammation that happens when there’s no injury or invader can harm healthy parts of the body and cause a range of chronic diseases  Types of inflammation Acute inflammation is sudden and temporary, may last for a few hours to a few days, depending on the condition. It is the immune system’s response to a sudden injury or illness. The symptoms of acute inflammation include:  Discolored or flushed skin.  Pain or tenderness that should be mild and only in the area of the injury.  Swelling (for example, knee inflammation).  Skin that feels hot to the touch.  Inability to use that part of the body as normally would (for example, reduced range of motion).  Chronic inflammation can go on for months or years, and can be harder to spot with a wide range of possible signs. It occurs when the body continues sending inflammatory cells even when there’s no danger Common symptoms of Chronic inflammation include:  Abdominal (belly) pain.  Chest pain.  Fatigue and/or insomnia.  Fever.  Joint pain or stiffness.  Mouth sores.  A skin rash.  Depression, anxiety and other mood disorders.  Gastrointestinal (GI) issues, like diarrhea, constipation and acid reflux.  Weight gain or weight loss.  Frequent infections.  Diseases associated with Chronic inflammation Autoimmune diseases, like lupus, rheumatoid arthritis (RA), psoriasis and ankylosing spondylitis (AS).  Cardiovascular diseases, such as heart disease and high blood pressure.  Certain cancers.  Gastrointestinal diseases, like Crohn’s disease and inflammatory bowel disease.  Lung diseases, like asthma and chronic obstructive pulmonary disease (COPD).  Mental health conditions, such as depression and anxiety.  Metabolic diseases, like Type 2 diabetes.  Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease.   The specific immune system: acquired/adaptive immunity  Diversity of antigens, Structure, properties and functions of antibodies  Cellular Immunity  Major Histocompatibility Proteins