Immune Response to Bacterial Infection, Imunopathology of Sepsis Jiří Litzman Factors influencing the extent and severity of infection •Pathogen factors •Dose •Virulence of organism •Route of entry •Host factors •Integrity of non-specific defences •Competence of the immune system •Genetic influences •Previous exposure to antigen •Existence of co-infection Immune mechanisms against bacterial infections •Non-specific immunity •Mechanical barriers •Phagocytosis •Complement system •Lysozyme •Defensins • Immune mechanisms against bacterial infections •Specific immunity •Antibodies – •Opsonization, •Activation of complement system, •Neutralization of toxins (e.g. antiphagocytic toxins), •Receptor blocade •Agglutination of microbes (respiratory tract) • •T-lymphocytes •Th1 lymphocytes- protection againts intracellular pathogens •Th2 lymphocytes – stimulation of antibody production •Th17 lymphocytes – pro-inflamatory effect Bacterial evasions of immune defences •Antiphagocytic machanisms: toxins, capsular polysaccharides •Inhibition of the complement system: Str. pyogenes, E. coli, N. meningitidis •Antigenic variations: Borrelia recurrentis •Proteases lysing IgA - Neisseria, Haemophilus •Sequestration in avascular regions- Salmonella typhi in the gall bladder and urinary tract •Intracellular parasitism Bystander damage caused by the immune response to bacterial infection •Autoimmune diseases •Cross-reactivity of bacterial and corporal antigens - rheumatic fever •Type-II hypersensitivity - autoimmune hemolytic anemia caused by Mycoplasma infection •Heat shock proteins •Superantigens (streptococcal, staphylococcal) •Immunocomplex diseases •Type IV hypersensitivity- cavitatoin in pulmonary tuberculosis Systemic Inflammatory Response Syndrome SIRS • Systemic inflammatory response in a wide range of severe clinical situations. •Characterized by at least 2 conditions: •Body temperature> 38 ° C or <36 ° C •Heart rate> 90 / min •Respiratory Frequency> 20 / min or PaCO2 <32mmHg •Leukocyte counts> 12 000 / mm3, <4 000 / mm3 or> 10% of immature form of granulocytes. •Sepsis: Systemic Inflammatory Response (SIRS) with proven infectious aetiology. • •Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion or hypotension. • •Septic shock: Sepsis induced hypotension despite adequate infusion therapy with abnormalities in organ perfusion. • Sepsis 3 The Third International Consensus Definition for Sepsis and Septic Shock (2016) • Sepsis - A life-threatening organ dysfunction caused by the dysregulation of host responses to infection. • • ("Severe sepsis" was omitted) Pathological immune consequences of sepsis •Severe inflammatory response • •Secondary immunosuppression Organ dysfunction in severe sepsis •Cardiovascular system: hypotension, metabolic acidosis, rise in lactate, oliguria •Respiratory system: decrease in Pa02, the rise of PaCO2 Hematologic abnormalities: decreased platelet count, DIC, leukocytosis, leukopenia •Nerve system: coma •Renal: increased creatinine •Hepatic: increased bilirubin, ALT Lipopolysaccharides (LPS) of G-bacteria - Endotoxins, •Are composed of lipid A (responsible for the biological activity), the cortex and the lateral polysaccharide chains. • Through the LPS-binding protein (LBP) binds to CD14 and TLT-4 on monocytes and macrophages and activates them. • A similar mechanism activates macrophages and peptidoglycan and teichoic acid of G+ of bacteria. Inflammatory response in sepsis •Formation of pro-inflammatory cytokines as a response to the stimulaci PAMPs (Pathogen-Associated Molecular Pattern) and DAMP (Damage Associated Molecular Pattern – alarmins). •Activation of the complement system formation of C3a, C4a. •Activation of the coagulation system, platelets. •Activation of endothelial cells leads to endothelial dysfunction with increased permeability. •NET(Neutrophil extracellular traps)osis of granulocytes Major mediators involved in the pathophysiology of sepsis •Proinflammatory: TNF-α, IL-1, IL-6, IL-8, PAF, IL-4, complement activation products • •Anti-inflammatory: IL-1RA, IL-10 • •The main effect outside the immune system: NO (hypotension, myocardial depression) • Tumor necrosis factor-α (TNF-α) in the pathophysiology of sepsis •Produced primarily by cell of the monocyto-macrophage lineages after endotoxin stimulation, GM-CSF, IFN-g •Causes a decrease of blood pressure, leukopenia with subsequent leukocytosis. Induces the formation of IL-1, IL-6, IL-8, subsequently NO (hypotension, pulmonary hypertension), acute phase proteins. •But: Complete blockade of TNF-α production leads to high animal mortality in experimental infection. In people treated with anti-TNF-α MP for rheumatoid arthritis, there was a clinical manifestation of tuberculosis. • • • • • Interleukin-1 in the pathophysiology of sepsis •Produced by monocyto-macrophage cell lineage. • •The inductors of production are endotoxin, TNF-α. IL-1 • •KO mice are resistant to the effect of endotoxin. • •Induces production of cytokines of an inflammatory response. IL-6 in the pathophysiology of sepsis • • •Produced by monocytes, macrophages, T-lymphocytes, fibroblasts, •endothelial cells. • •It is a differentiation factor of B lymphocytes and a T lymphocyte activation factor. • •It acts pyrogenically, induces the formation of acute phase proteins. • •In some studies, IL-6 levels correlated with patients mortality. Secondary immunodeficiency in sepsis (formerly Compensatory Anti-Inflammatory Response Syndrome-CARS) •Some patients in sepsis pass from the "hyperinflammatory" phase to a state of low immune response (immunoparalysis). •Anti-inflammatory responses include IL-4, IL-10, IL-11, IL-13. •Changes in antigen-presenting cells of low expression of HLA-DR on monocytes. •Decrease in T-cell count is due to increased apoptosis. • Lymphocytic exhaustion occurs. Th2 predominance. •High PD1 (Programmed Cell Death) expression on lymphocytes and its ligands (PD1L) on macrophages and granulocytes. •The production of proinflammatory cytokines TNF-α, IL-1, IL-6, IL-8 is reduced. schema_2_1-01.png Activation of TCR by antigen and superantigen MHC class II Signal transduction Superantigen T cell APC TRC Signal transduction α β α β α β α β Antigen The most important superantigens •S. aureus: Enterotoxin and toxin toxic shock syndrome •Str. pyogenes: pyrogenic (erythrogenic) toxins, M protein •Clostridium perfringens: enterotoxin •superantigens of mycoplasma, Pseudomonas, Yersinia enterocolitica, Mycobacterium tuberculosis • • • • The toxic shock syndrome • •The toxic shock syndrome can most often occur in people infected with staphylococci. •The superantigen toxic shock toxin (TSST-1 - Toxic Shock Syndrome Toxin-1) is crucial in the pathogenesis. •Massive production of cytokines in particular leads to the development of shock and multi-organ failure. • • • •