21 Immune mechanisms of inflammation local and systemic

21. Immune mechanisms of inflammation (local and systemic reaction). 22. Physiological mechanisms of regulation of the immune system. Cytokines (classification according to the function). 23. Defence against extracellular pathogens. 24. Defence against intracellular. 25. Anti-viral defence. 26. Defence against multicellular parasites.

Inflammation

Inflammation Is a physiological response of the organism to harmful stimuli, leading to localization of damage, elimination of pathogens, necrotic cells… and initiation tissue repairing.

Causes of inflammation § Physical injury § Infection by pathogens § Damage caused by chemicals § Cancer § Alergic disease § Autoimmune disease

Inflammation acute (physiological reactions, damaged tissue heals completely) chronic (usually pathological reactions, destruction of tissue and compensation with fibrous tissue) Response of the organism local systemic

Local body's response to inflammation Signs - pain (dolor), heat (calor), redness (rubor), swelling (tumor)

Local inflammation The first signals for the development of inflammatory reactions originate from activated phagocytes, mast cells, complement and substances released from damaged cells and extracellular matrix components.

Local inflammation

Local inflammation § vasodilation and increased vascular permeability (histamine, serotonin, bradykinin, complement components C 3 a, C 5 a, leukotrienes, prostaglandins) => redness and swelling § increased expression of adhesion molecules on endothelial cells (TNF, IL-1) => capture leukocytes and phagocytes § influence nociceptors (prostaglandins, . . . ) => pain § Increase temperature (IL- 1, IL-6, TNF, prostaglandins)

Systemic inflammation § leukocytosis § fever (TNFa, IL-1, IL-6, IFN ) § ↑ tissue metabolism § ↑ mobility of leukocytes § ↑ IFN, cytokines and Ig production § ↑ expression of Hsp § acute phase proteins (IL-6, TNF, IL-1)

Acute phase proteins produced by hepatocytes: § CRP - opsonization, complement activation § SAA - attracting leukocytes § C 3, C 4 § protease inhibitors - protection against secondary tissue damage § serum transport proteins

Systemic inflammation Septic shock - the massive penetration of microorganisms into the bloodstream ( TNF) Anaphylactic shock - basophil degranulation after contact with allergen (histamin)

Repair of damaged tissue § after the elimination of pathogens and damaged cells by phagocytes § activation of angiogenesis § regeneration and tissue remodeling (fibroblasts, smooth muscle cells, keratinocytes, epithelial cells) § regulated by cytokines: PDGF, TGFb (platelets, macrophages. . . )

Physiological regulation of the immune system

Physiological regulation of the immune system § Regulation by antigen § Regulation by antibodies § Regulation by cytokines and cellular contact § Suppression mediated by T cells § Other factors influencing the outcome of the immune response § Regulation by cytokines

Regulation by antigen § Immune responses induction and extinction § Affinity maturation of B lymphocytes § Maintaining immunological memory § Antigenic competition § Threshold density of the complex MHC II-gp Ag on APC

Regulation by antibodies § Antibodies competes with the BCR for antigen (negative regulator of B lymphocyte stimulating) § Ig. G immune complexes bind to the BCR and Fc R on B cells, resulting in blocking of B cell activation § Regulation via idiotypic network

Regulation by cytokines and cellular contact § Interaction APC - T lymphocyte § Interaction TH 1 – macrophages § Interaction TH 2 - B lymphocytes § Mutual regulation of activity TH 1 versus TH 2 § Development of leukocyte subpopulations Negative regulation of effector cells: § CTLA-4 - T cell inhibitory receptor, binds ligands CD 80 and CD 86 § Inhibitory receptors of NK cells § Self-destruction interaction of the apoptotic receptor Fas with ligand Fas. L on the surface of activated T lymphocytes

Suppression mediated by T cells § Mutual negative interactions mediated by Th 1 and Th 2 cytokines (Th 2 cells produce IL-4 and IL-10 which suppress the immune response, based on TH 1 cells) § Clonal elimination or anergition of T cells after antigen recognition on the surface of other cells than APC (lacking co-stimulatory signals) § Regulatory T cells maintain tolerance to autoantigens (Treg, Tr 1)

Factors influencing the outcome of the immune response The same antigen can induce an active immune response or an active state of tolerance, the result of response depends on many factors: § State of the immune system § Properties of antigen § Dose of antigen § Route of antigen administration

Cytokines (Tissue hormones)

Cytokines § Regulatory proteins and glycoproteins produced by leukocytes and other cells § Essential regulators of the immune system § Apply outside the immune system (angiogenesis, tissue regeneration, carcinogenesis, treatment of many brain functions, embryonic development. . . ) § Cytokines - secreted - membrane (CD 80, CD 86, CD 40 L, Fas. L. . )

Cytokines § Pleiotropic effect § Operates in a cascade § Cytokine Network § Cytokine system is redundant § Effects of cytokines - autocrine - paracrine - endocrine § Are known as interleukins (exception: TNF, lymphotoxin, TGF, interferons, CSF and growth factors)

Distribution of cytokines by function 1) Proinflammatory cytokines (IL-1, IL-6, IL- 8, IL- 12, IL- 18, TNF) 2) Antiinflammatory cytokines (IL-4, IL-10, TGF ) 3) Cytokines with the activity of hematopoietic cells growth factor (IL-2, 3, 4, 5, 6, 7, 9, 11, 14, 15, CSF, SCF, LIF, EPO) 4) Cytokines applying in TH 2 humoral immunity (IL-4, 5, 9, 13) 5) Cytokines applying in the cell-mediated immunity TH 1 (IL-2, 12, IFN , GM-CSF, lymphotoxin) 6) Cytokines with antiviral effect (IFN- , IFN- �, IFN- )

Overview of the most important cytokines Cytokine Produced Function IL-1 MF, N T cell costimulation, induction of TNF and IL-8, pyrogen IL-2 Th 1 Growth factor for T cells IL-4 Th 2, basophils Th 2 differentiation, B cell stimulation, isotype switching to Ig. E and Ig. G 4, Th 1 inhibition IL-5 Th 2, eosinophils B cell stimulation, growth factor for eosinophils IL-6 Th 2, MF, N T and B cell stimulation, stimulation of Ig production, induction of acute phase proteins synthesis, pyrogen IL-8 MF, other cells Granulocyte activation and chemotaxis (primarily neutrophils) IL-10 Th 2, M, Treg Th 1 and MF inhibition, B cell differentiation to plasma cell IL-12 MF, DC, B Th 1 differentiation, NK stimulation TNF M, MF, NK Induction of local inflammation, endothelium activation, induction of apoptosis TGFb T, MF, platelets The anti-inflammatory effect (control of lymphocyte proliferation, control of Ig production, control MF activity), stimulation of fibroblasts and osteoblasts, gain production of extracellular matrix IFNa L, M, MF Inhibition of viral replication IFNb Fibroblasts, epithelial cells Inhibition of viral replication IFN Th 1, NK MF activation, stimulation of MHC gp. expression, Th 2 inhibition MF – macrophages; M – monocytes; N – neutrophils; DC – dendritic cells; NK – natural killers; L – lymphocytes; B – B cell; T – T cell

Cytokine receptors § Consisting of 2 or 3 subunits § One subunit binds cytokine, other are associated with cytoplasmic signaling molecules (protein kinases) § Signaling subunit is shared by several different cytokine receptors - called receptor family § Signaling through these receptors may lead to proliferation, differentiation, activation of effector mechanisms or blocking the cell cycle and induction of apoptosis

Defense against extracellular pathogens

Defence against extracellular pathogens § bacteria (gram-negative, gram-positive cocci, bacilli), unicellular parasites § pathogens induce inflammation § removed by phagocytosis - neutrophil granulocytes § opsonization (Ig. G and Ig. A antibodies, C 3 b, lectins, CRP. . . )

Defence against extracellular pathogens Opsonisation and phagocytosis

Defence against extracellular pathogens § Phagocytes are attracted to the site of infection by chemotactic substances (C 5 a, C 3 a and chemotactic products of bacteria…) § ingested bacteria are destroyed by the microbicidal systems (products of NADP-H oxidase, hydrolytic enzymes and bactericidal substances in lysosomes) § phagocytes produce proinflammatory cytokines (IL-1, IL-6, TNF)

Defence against extracellular pathogens § Ig. M - complement activation § Ig. G - activation of complement, opsonization § Ig. A - opsonization s. Ig. A prevents against infection by intestinal and respiratory bacteria § in the defense against bacterial toxins apply neutralizing antibodies (Clostridium tetani and botulinum …)

Defence against extracellular pathogens § "indirect toxins - bacterial Lipopolysaccharide (LPS) stimulates big number of monocytes to release TNF, which can cause septic shock § individuals with immunodeficiency of phagocytes, complement and antibodies production are especially at risk of infections with extracellular bacterial

Defense against intracellular pathogens

Defense against intracellular pathogens § bacteria, fungi and unicellular parasites § intracellular parasites are resistant to the microbicidal mechanisms of phagocytes § macrophages, which absorbed them, produce IL-12 → TH 1 differentiation, production of IFN and membrane TNF → activation of macrophages and production of NO

Defense against intracellular pathogens

Defense against intracellular pathogens § TC lymphocytes apply in the defense against intracelular parasites, which escape from phagolysosomes § individuals with certain disorders of phagocytes and defects of T lymphocytes are at risk of infections with intracellular microorganisms

Defense against intracellular pathogens

Anti-viral defense

Anti-viral defence § interferons - production of IFN and IFN is induced in infected cells; IFN activates macrophages (i. NOS) § IFN and IFN - prevents viral replication - induce proliferation of NK cells - increase the expression of HLA-I

Anti-viral defence - interferons

Anti-viral defence § NK cells - ADCC (Antibody-dependent cell-mediated cytotoxicity); NK cell bind with CD 16 (Fc receptor) to Ig. G which has bound to the surface of infected cell and then NK cell release perforins and granzymes (degranulation) § infected macrophages produce IL-12 (a strong activator of NK cells)

Anti-viral defence - NK cell activation ADCC

Anti-viral defence § in the defense against cytopathic viruses applied antibodies: § s. Ig. A inhibit mucosal adhesion of viruses (defense against respiratory viruses and enteroviruses) § neutralizing Ig. G and Ig. M antibodies activate the classical pathway of complement, that is able to lyse certain viruses § opsonized viral particles are phagocytosed § Ig. A and Ig. G have preventive effect in secondary viral infection

Anti-viral defence - antibodies

Anti-viral defence § effector TC lymphocytes destroy infected cells in direct contact (granzym/perforin; Fas. L) and by produced cytokines (lymfotoxin) § some viruses after infection integrate into the host genome, where persist for years (varicella zoster, EBV, papillomavirus) § individuals with T lymphocyte immunodeficiency and with combined immune disorders are at risk by viral infections § increased susceptibility to herpes infections in individuals with dysfunction of NK cells

Anti-viral defence – NK cells and Tc lymphocytes

Defense against multicellular parasites

Defense against multicellular parasites § Ig. E, mast cells, basophils and eosinophils § TH 2 stimulation under the influence of IL-4 (mast cells and other APC stimulated by parasite) § TH 2 stimulate B cells with BCR-specific parasite antigens § isotype switching under the influence of IL-4 to Ig. E § Ig. E bind to Fc RI on mast cells and basophils

Defense against multicellular parasites § multicellular parasite binds to Ig. E on mast cell→ crosslinking of several molecules Fc RI § initiate mast cell degranulation (release of histamin, tryptase, serotonin…) § activation of arachidonic acid metabolism (leukotriene C 4, prostaglandin PGD 2) - amplification of inflammatory responses § cytokine production by mast cell (TNF, TGF , IL-4, 5, 6)

Defense against multicellular parasites Histamine § vasodilatation, increase vascular permeability (erythema, edema, itching) § bronchoconstriction (cough) § increases intestinal peristalsis (diarrhea) § increased mucus secretion This helps eliminate the parasite.

Mast cell activation

Defense against multicellular parasites § eosinophils fagocyte complexes of parasitic particles with Ig. E via their receptors for Ig. E § eosinophils use against parasites extracellular bactericidal substances released from granules (ECP- eosinophil cationic protein, MBP-major basic protein…)

Defense against multicellular parasites - eosinophils

Thank you for your attention

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