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Innate and adaptive immunity
Innate and adaptive immunity
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  1. 1. Systemic effects of inflammation
  2. 2. 1. Introduction: • Inflammation is local response of live and vascularized animal tissue to injury from any agent which could be microbial, immunological, physical or chemical… • The effects of inflammation can be both local or systemic. • Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the repair process can themselves cause considerable harm.
  3. 3. .. • Systemic effects of inflammation are mediated by both: Cell derived mediators: TNF, IL1, IL-6. Plasma cell derived mediators: fibrinogen. • Those effects can be due to acute or chronic inflammation.
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  5. 5. 2-Systemics effects of inflammation 1. Fever, 2. Elevated levels acute phase proteins, 3. Leukocytosis, 4. Anemia, 5. Systemic Response Inflammatory Syndrome (SIRS). 6. Compensatory anti-inflammatory Response Syndrome( CARS). 7. Others ( sepsis, ARDS, wasting syndrome).
  6. 6.  Fever • Defined as an elevation of body temperature above normal circadian variation. • For every 1C over 37C, 13% increase of oxygenation consumption. • Body temperature is controlled by hypothalamus ( peri-optic/post). • Occurs with an increase in the hypothalamus set point. • Produced in response to substances called: Pyrogens either endogenous or exogenous.
  7. 7. … • Bacterial products, such as Lipopolysacchrides (LPS) in gram negative bacteria (exogenous pyrogens), • Stimulate leukocytes to release cytokines such as IL-1 and TNF (endogenous pyrogens), • Increase the enzymes cyclooxygenases that convert Arachidonic acid into prostaglandins. • In the hypothalamus, the prostaglandins, especially PGE 2 , stimulate the production of neurotransmitters such as cyclic AMP. • Which function to reset the temperature set-point at a higher level.
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  10. 10. Reminder
  11. 11.  Elevated acute phase proteins: • Are defined as those proteins whose serum concentrations increase or decrease by at least 25 percent during inflammatory states. Such proteins are termed either positive or negative APP. • Mostly are plasma proteins synthesized in the liver. • Their plasma concentrations may increase to 1000-fold as part of the response to inflammatory stimuli; Examples: 1. C-reactive protein (CRP), 2. Fibrinogen, 3. Serum Amyloid A protein (SAA).
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  14. 14. FUNCTIONS • Trapping of micro-organisms and their products • Activation of the complement system eg crp • Neutralizing enzymes • Scavenging free hemoglobin and radicals eg haptoglobin • Binding cellular remnants like nuclear fractions
  15. 15. 1- C- reactive protein • It’s an annular pentameric polypeptide synthesized by liver (hepatocytes) in response to inflammation. • Stimulate secretion of pro-inflammatory cytokines (IL-6,TNF,adhesion molecule, endothelin 1 by endothelial cells). • CRP bind to microbial cell walls (phosphorylcholine) they may act as opsonins and activate the complement system and bind to phagocytic cells via Fc receptors, suggesting that it can initiate elimination of pathogens.
  16. 16. 2- fibrinogen • As it called factor I, glycoprotein circulates in the blood of vertebrates. • During injury it is converted enzymatically by thrombin into fibrin during blood clot formation. • Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual erythrocytes. • This is the basis for measuring the erythrocyte sedimentation rate (ESR) as simple test for systematic inflammation response by number of stimuli e.g.Lipopolysacchrides
  17. 17. 3- Serum Amyloid A (SAA) • A major human acute phase protein family, are apolipoproteins that are rapidly associated with high-density lipoprotein following their synthesis and secretion and can influence cholesterol metabolism during inflammatory states. • SAA may increase the adhesion and chemotaxis of phagocytic cells and lymphocytes. • Also it’s an acute phase marker that respond rapidly, associated more with joint disease eg: rheumatoid arthritis. • it has been associated as marker for: Cardio-vascular diseases, Obstructive sleep apnea, Coronary heart diseases.
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  19. 19.  Leukocytosis: • Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infection. • The leukocyte count usually climbs to 15,000 or 20,000 cells/µl, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/µl. [normal 4,000-11000 cells/µl]. • The leukocytosis occurs initially because of accelerated release of cells from the bone marrow (caused by cytokines, including IL-1 and TNF) • therefore associated with a rise in the number of more immature neutrophils in the blood.
  20. 20. .. • Prolonged infection also induces proliferation of precursors in the bone marrow, caused by increased production of colony stimulating factors (CSFs). • Bone marrow output of leukocytes is increased to compensate for the loss of these cells in the inflammatory reaction.
  21. 21. … • Neutrophilia refers to an increase in the blood neutrophil count due to bacterial cause mostly. • Lymphocytosis due to viral infections: infectious mononucleosis, mumps… • Eosinophilia seen in bronchial asthma, hay fever, and parasitic infestations, malaria….
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  23. 23.  Anemia: • Anemia of chronic inflammation is defined as normochromic, normocytic hypo-proliferative. • could be due to decreased red cell survival (RBC mass) which may occur in cases of acute inflammation characterized by increased marcro-phage activity. • The release of cytokines IL-1/ IL-6 and TNF alpha may decrease bone marrow responsiveness to erythropoietin, which may induce apoptosis or red cell precursors. • 33-60% patients with rheumatoid arthritis developpe anemia.
  24. 24.  Systemic inflammatory response syndrome: • SIRS is nonspecific reaction and can be caused by infectious or non infectious agents. • Although inflammation is an essential component of host defense against different insults, SIRS develops only when localized aggressive injury process gains access through blood stream and lymphatic to the whole body.
  25. 25. 1- Epidemiology • The true incidence of systemic inflammatory response syndrome (SIRS) is unknown but probably very high, owing to the nonspecific nature of its definition. • Not all patients with SIRS required hospitalization or have disease that progress to serious illness. • Rangel-Fausto et al published a prospective survey of patients admitted to a tertiary care center that revealed 68% of hospital admissions to surveyed units met SIRS criteria.The incidence of SIRS increased as the level of unit acuity increased. The following progression of patients with SIRS was noted: 26% developed sepsis, 18% developed severe sepsis, and 4% developed septic shock within 28 days of admission.
  26. 26. … • Another study demonstrated that 62% of patients who presented to the emergency department with SIRS had a confirmed infection, while 38% did not. Within the same cohort of patients, 38% of infected patients did not present with SIRS.
  27. 27. 2- Diagnostic criteria • Criteria for SIRS are considered to be met if at least 2 of the following four clinical findings are present: 1. Temperature >38°C or <36°C 2. Heart rate HR > 90 beats/min 3. Respiratory rate > 20 breaths/min OR PaCO2 < 32 mmhg 4. WBC > 12,000/ul OR <4000/ul OR with 10% immature band forms.
  28. 28. 3- Etiology of SIRS • Can be grouped into two : Pathogenic such as bacterial, fungal or viral. Non-pathogenic such as trauma, radiation , chemical.
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  30. 30. 4- Pathophysiology of SIRS: • The transition from local inflammation response to SIRS can be staged into three: Stage 1: Insult cytokines release cellular inflammatory response repair and recruitment of Reticular endothelial system  (local inflammation- rubor, tumor, dalor, calor and functio laesa).
  31. 31. … • Stage 2: Cytokines circulation  stimulation of growth factors +macrophages and platelets recruitment. Acute phase response-controlled by ↓proinflammatory mediators + release of endogenous antagonists. Manifestation; minimal malaise and low grade fever.
  32. 32. …. • Stage 3:  No Homeostasis restoration + Inflammatory stimuli continue to exert its effect in systemic circulation significant systemic reaction.  Cytokines released destruction rather than protection  activation of numerous humoral cascades and reticular endothelial system + loss of circulatory integrity –End organ Failure.
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  34. 34. .. • Infectious insult(or others) Tissue macrophages, monocytes, mast cells, platelets, and endothelial cells to produce a multitude of cytokines. • The cytokines -TNF-α & IL-1 are released first (responsible for majority of systemic effects e.g fever). • NOTE; Infection has been shown to induce a greater release of TNF-α —thus inducing a greater release of IL-6 and IL-8—than trauma does. This is suggested to be the reason higher fever is associated with infection rather than trauma.
  35. 35. … • IL-1 & TNF-α  cleavage of the nuclear factor-kB (NF-kB) inhibitor. • NF-kB production of mRNA  induces the production other proinflammatory cytokines , IL-6, IL-8, and interferon gamma being the primary ones. • IL-6, stimulate the release of acute-phase reactants such as C-reactive protein (CRP), Fibrinogen and procalcitonin.
  36. 36. … • ↑CRP and (SAA-from IL1 & TNF-α )bind to microbial cell walls  opsonization ,fix to the complement promoting the elimination of the microbes by phagocytosis. • Elevated serum levels of CRP are now used as a marker for increased risk of myocardial infarction or stroke in patients with atherosclerotic vascular disease.
  37. 37. … • Fibrinogen binds to erythrocytes  forms stacks (rouleaux) that sediment more rapidly at unit gravity than individual erythrocytes. • This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a simple test for the systemic inflammatory response, caused by any stimuli.
  38. 38. … • In response to infection or injury, as is seen with SIRS, HMGB1(High mobility group box, a protein present in the cytoplasm and nuclei in a majority of cell types) is secreted by innate immune cells and/or released passively by damaged cells. • acts as a potent proinflammatory cytokine and is involved in delayed endotoxin lethality and sepsis
  39. 39. 5- Role of complement • Protein complements, C3a and C5a have been the most directly responsible in release of additional cytokines and to cause vasodilatation and increasing vascular permeability.
  40. 40. 6- Coagulation and DIC: • IL-1 and TNF-α  endothelial surfaces  expression of tissue factor production of thrombin  promoting coagulation (Thrombosis). • On the other end Fibrinolysis is impaired by IL-1 and TNF-α via production of plasminogen activator inhibitor-1. • the widespread micro vascular thrombosis consumes platelets and coagulation proteins initiating Fibrinolysis cascades hence DIC.
  41. 41.  Compensatory-inflammatory response syndrome: • The body is equipped to reverse and counteract the acute inflammatory response via CARS. • IL-4 and IL-10 are cytokines responsible for decreasing the production of TNF-α, IL-1, IL-6, and IL-8. • The acute phase response also produces antagonists to TNF-α and IL-1 receptors. • These antagonists either bind the cytokine, and thereby inactivate it, or block the receptors. • The balance of SIRS and CARS helps determine a patient's outcome after an insult.
  43. 43.  Sepsis: • Refers to symptomatic presence of bacteria in the blood with or without organ dysfunction. • Its pathophysiology is the same as that of SIRS.
  44. 44. … • septic shock triad: Due to production of TNF can be responsible of : 1-DIC, 2-metabolic disturbances including acidosis and hypoglycemia. 3-cardiovascular failure e.g :hypotensive shock.
  45. 45.  Acute respiratory distress syndrome ARDS: • clinical syndrome caused by diffuse alveolar capillary and epithelial damage. • The same physiopathology as in SIRS
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  47. 47.  Wasting syndrome: • It is involuntary loss of weight, muscle atrophy ,fatigue, weakness. • Its among chronic inflammation systemic effects. • Results from TNF-mediated appetite suppression and mobilization of fat stores. • Altering circulating levels of hormones that regulate muscle growth and affects tissue sensitivity to such factors.
  48. 48. References • Lewis J K. SIRS Medscape 2018. • Cytokines in the systemic inflammatory response syndrome: a review by U.Jaffer, R.G.Wade, T.Gourlay. • Up-to-date. • Robbins Basic Pathology 8th /9th edition. • Harsh Mohan Text book of Pathology; 6th edition. • Acute-phase proteins and other systemic responses to inflammation.https://www.ncbi.nlm.nih.gov/pubmed/9971870 • Acute Phase Reactants www.tip.hacettepe.edu.tr/actamedica/2013/Acta13(2).pdf
  49. 49. … Thank you

Notas do Editor

  • Infectious agent/ microbial products as well as cytokines and other inflammatory process, induce macrophage and other cell to produce and secrete pyrogenic cytokines into circulation.
    These pyrogenes induce synthesis of PGE2 in the hypothalamus. In addition microbial toxine acting as ligands to the TLR in the hypothalamus stimulate the PGE2 RAISES THE THERMOStatic set point , vaspmoteur center sends signal for hear conservation vasoconstriction and heat production shivering .