Chapter 75 – Immune System




Abstract




An antigen is a substance that stimulates the immune system, resulting in an immune response. Antigens are either proteins or polysaccharides. The immune system produces antibodies that specifically bind to the antigen.





Chapter 75 Immune System




What is an antigen? How does an antigen differ from a hapten and an allergen?


An antigen is a substance that stimulates the immune system, resulting in an immune response. Antigens are either proteins or polysaccharides. The immune system produces antibodies that specifically bind to the antigen.


A hapten is a small molecule that may also stimulate the immune system, but only when attached to a larger carrier protein. The immune system produces antibodies to the hapten–carrier complex; these antibodies can also bind to the hapten (when not attached to a carrier protein).


An allergen is an environmental antigen that produces a vigorous immune response, even though the allergen is usually harmless.



What are the differences between the innate and adaptive immune systems?


The role of the immune system is to defend the body against microorganisms, abnormal host cells, toxins and other foreign material. The two main parts of the immune system are the innate and adaptive immune systems.




  • Innate immune system. Key features are:




    1. Immediate line of defence.



    2. Rapid but non-specific response to a potential threat. No previous exposure to an invading microorganism is required.



    3. Composed of several parts:




      1. Anatomical/biochemical – including skin, mucociliary escalator of the respiratory tract, low gastric pH, peristalsis and biliary secretions of the gastrointestinal tract. Lysozyme secretion in saliva and tears causes bacterial cell wall lysis. Transferrin secretion in mucosa creates a low-iron environment, thus inhibiting bacterial replication.



      2. Inflammation.



      3. Complement system.



      4. Cellular components – neutrophils, macrophages, natural killer (NK) cells, mast cells, basophils and eosinophils.



      5. Acute-phase proteins; for example, C-reactive protein, α1-antitrypsin.





  • Adaptive immune system. Key features are:




    1. Slower response, but specific to the invading microorganism. The adaptive immune response is slower than the innate immune system, but has the advantage of ‘memory’ – a much quicker response occurs if the same microorganism invades for a second time.



    2. Involvement of both cellular and humoral elements:




      1. Cytotoxic T cells are responsible for cell-mediated immunity – defence against intracellular pathogens and abnormal host cells.



      2. B cells and T helper cells are responsible for antibody-mediated (humoral) immunity – defence against pathogens within body fluids.





Which cells are involved in the innate immune response?


The innate immune response involves different types of white blood cells (leukocytes):




  • Neutrophils account for 60% of all leukocytes. They are involved in the phagocytosis (engulfing and ingestion) of bacteria and fungi. A neutrophil can phagocytose around 5–20 bacteria before it dies.



  • Monocytes migrate from blood into tissues, where they become macrophages. Macrophages phagocytose microorganisms and cellular debris. A macrophage may phagocytose up to 100 bacteria before it dies.



  • Eosinophils are involved in the killing of multicellular microorganisms, such as helminths and parasites. Eosinophils (along with mast cells) are also important in the pathogenesis of allergic reactions and asthma (serum eosinophil count increases in both conditions).



  • Basophils are the least common of the leukocytes. Basophils seem to act like circulating mast cells: they have granules that contain inflammatory mediators, including histamine and heparin. Basophils are involved in allergic reactions and defence against parasites.



  • NK cells are classed as lymphocytes, but in contrast to the other lymphocytes (B and T cells), NK cells are non-specific in their immune function. NK cells are extremely important: they destroy tumour cells and cells infected with viruses. They are also thought to be involved in the suppression of a pregnant mother’s immune system to prevent immune attack of the foetus.



What is inflammation?


Inflammation is a non-specific response triggered by either microorganism invasion or tissue injury. First described over 2000 years ago, the symptoms of inflammation are redness, heat, swelling and pain. Inflammation is characterised by the following processes:




  • Vasodilatation, which increases blood flow to the site of injury/infection, thus explaining the redness and heat associated with inflammation.



  • Increased vascular permeability, which allows plasma proteins to leak from the vessels to the site of injury/infection. The leak of plasma to the interstitial space accounts for the oedema associated with inflammation.



  • Migration of phagocytes, which kill invading microorganisms and remove debris in preparation for tissue healing.


Inflammation can be initiated by a number of insults. The mechanisms of initiation are complex and not fully understood. A simplified sequence of events is:




  • Recognition of tissue damage. The two most common causes of tissue damage are trauma and infection. The body recognises these threats in different ways:




    1. Trauma. Mechanical damage causes blood vessel disruption and local mast cell degranulation. Blood vessel disruption activates platelets and the coagulation cascade (see Chapter 72), whilst mast cells release histamine and other inflammatory mediators.



    2. Infection. Tissue macrophages recognise the presence of microorganisms. In addition to phagocytosing the microorganisms, macrophages release proinflammatory cytokines including interleukins-1 and -6, and tumour necrosis factor-α (IL-1, IL-6 and TNF-α, respectively) that trigger local mast cells to degranulate, releasing more proinflammatory cytokines.




  • Local inflammatory response. Irrespective of the mechanism of initiation, inflammation follows a stereotypical series of events:




    1. Local arterioles vasodilate in response to histamine. This increases blood flow to the area of injury, thus delivering the necessary quantities of leukocytes and plasma proteins.



    2. Post-capillary venules increase their permeability. These venules already have very thin walls with little muscle or connective tissue. The vessels swell in response to proinflammatory cytokines, mainly TNF-α and histamine, allowing gaps to develop between endothelial cells. Large volumes of plasma, including large molecules such as complement, coagulation proteins and, later on in the inflammatory process, antibodies, pass into the interstitial space. Complement acts in two main ways (see below): by triggering further degranulation of mast cells and through opsonisation (coating) of microorganisms to facilitate their phagocytosis.



    3. Recruitment of cellular components. The increased permeability of the post-capillary venules is not in itself a sufficient signal to induce leukocytes to migrate into the interstitial space. Capillaries’ endothelial cells need a way of signalling to passing leukocytes, informing them of a pathogen threat. In response to inflammatory mediators, endothelial cells express cell surface adhesion molecules that slow down circulating neutrophils and macrophages, allowing them to pass between the endothelial cells in a process known as ‘transmigration’. The leukocytes are then guided towards the site of injury/infection by attractant molecules called chemotactic molecules.




  • Systemic inflammatory response. Proinflammatory cytokines are usually concentrated at the site of injury/infection. However, in severe inflammation or in cases where a microorganism escapes from the site of invasion, proinflammatory cytokines are released into the systemic circulation, causing:




    1. Pyrexia which augments phagocytosis and impairs bacterial multiplication.



    2. Release of neutrophils from the bone marrow.



    3. Release of acute-phase proteins from the liver: plasma C-reactive protein concentration correlates with the degree of inflammation.




What are eicosanoids and kinins? How are these involved in inflammation?




  • Eicosanoids are a family of signalling molecules whose main role is that of a proinflammatory cytokine. Eicosanoids are all derived from arachidonic acid and are subclassified into prostaglandins, prostacyclins, thromboxanes and leukotrienes. One of the enzymes involved in the synthesis of prostaglandins, prostacyclins and thromboxanes is cyclo-oxygenase (COX; also termed prostaglandin-endoperoxide synthase). The COX-1 and COX-2 enzymes are important targets for the clinical management of inflammation.



  • Kinins are poorly understood. During acute inflammation, bradykinin is produced through cleavage of inactive precursors. Like histamine, bradykinin causes arteriolar vasodilatation and increases the permeability of post-capillary venules. Bradykinin is also implicated in the sensitisation of peripheral pain fibres.




Clinical relevance: systemic inflammatory response syndrome


Following severe tissue damage or infection, inflammation can spiral out of control when proinflammatory cytokines are released into the systemic circulation. Systemic inflammatory response syndrome (SIRS) results from this cytokine storm and is defined by two or more of the following signs:




  • Pyrexia > 38°C (or < 36°C);



  • Heart rate > 90 bpm;



  • Respiratory rate > 20 breaths/min;



  • White cell count > 12 × 109/L or < 4 × 109/L.


The same stereotyped processes that usually only occur local to the site of tissue damage now spread to the whole body, resulting in:




  • Generalised vasodilatation and leaky post-capillary venules. This leads to systemic hypotension and intravascular fluid depletion, respectively.



  • Neutrophil migration into organs distant to the site of infection/injury.



  • A pro-coagulant state, resulting in microvascular thrombosis.



  • Myocardial depression, probably due to delayed Ca2+ uptake and release by the sarcoplasmic reticulum.



  • Mitochondrial dysfunction, resulting in a failure of oxidative phosphorylation.


As many of these complications result in reduced O2 delivery to the tissues, it is no surprise that patients with SIRS may go on to develop multiple organ dysfunction. Organ dysfunction is usually a combination of macro- and micro-vascular ischaemia. The lung is the most common organ to malfunction in response to systemic inflammation, leading to acute respiratory distress syndrome. Note: SIRS is most commonly triggered by severe infection (especially Gram-negative infection), but is also triggered by non-infective aetiology, such as acute pancreatitis and severe trauma.



What are the roles of complement?


The complement system is a collection of 25 plasma proteins. Although it is considered part of the innate immune system, the complement system also contributes to the adaptive immune system, as it ‘complements’ the activity of antibodies. The complement system may be activated in two ways:




  • Coming into contact with a particular type of bacterial cell wall – this is called the alternative pathway.



  • Exposure to an antibody–antigen complex – this is called the classical pathway.


Once activated, complement has a number of roles:




  • Bacterial cell lysis. Many activated complement proteins come together to form a ‘membrane attack complex’. This complex kills bacteria by punching holes in their cell membranes. Water diffuses along its osmotic gradient through these holes, causing the bacteria to swell and burst.



  • Opsonisation. Fragments of complement protein coat the microorganisms and then act as binding sites for neutrophils and macrophages, making phagocytosis more efficient.



  • Chemotaxis. After leukocytes migrate into the tissues from the circulation, bits of complement act as homing beacons, guiding leukocytes towards the site of infection.



  • Triggering local mast cells to degranulate, releasing vasoactive mediators such as histamine, thus augmenting inflammation.

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Sep 27, 2020 | Posted by in ANESTHESIA | Comments Off on Chapter 75 – Immune System
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