Introduction to Immunology Martin Liška

The immune system and its importance for homeostasis of organism The immune system = a system of non-specific and specific mechanisms protecting the organism from damage caused by infectious factors of environment and providing surveillance of own structures (elimination of damaged and death cells) The aim is maintenance of homeostasis and integrity of macroorganism

Mechanisms of immune system and their cooperation 1/ Innate (non-specific) immune system innate, not developed after the exposition to infection uniform response, prompt, no immunological memory mechanical barriers (mucosa, skin) phagocytic cells (microphages, macrophages) acute phase proteins (CRP) complement system

Mechanisms of immune system and their cooperation 2/ Adaptive (specific) immune system adaptability, developed after the exposition to infection the immune response is not inherited, immunological response B and T cells, immunoglobulins

The components of immune system 1/ Cells a/ innate immune system neutrophils, eosinophils, basophils macrophages nature killer cells (NK cells) b/ adaptive immune system - lymphocytes

The components of immune system 2/ Organs liver, skin etc. primary lymphoid organs – bone marrow, thymus - secondary lymphoid organs - spleen, lymph nodes, mucus associated lymphoid tissue (MALT)

The components of immune system 3/ Substances The complement system Cytokines – molecules which ensure the communication between the components of immune system (e.g.IFN, IL, growth factors) Acute phase proteins (CRP, MBL) Hormones (immunostimulatory/immunesuppressive effects) Immunoglobulins

The immune system of mucosa and skin intact surface, clearance of surface (microcillia, saliva, tears, urine) lysozyme IgA lymphoid tissue of mucosa (MALT) macrophages (dendritic cells)

The immune system of mucosa and skin intact surface lipid barrier (eczema) immunocytes of the skin (e.g. Langerhans cells)

Non-specific immune mechanisms 1/ Barriers see above (skin, mucosa) secretions (fatty acids, HCl, lysozyme) 2/ Various physiological mechanisms body temperature hormones

Non-specific immune mechanisms 3/ Phagocytosis the process by which particular substances or cells are ingested and destroyed by specialized cells neutrophils, macrophages (monocytes, tissue macrophages)

Neutrophils The most abundant population of leucocytes (cca 70%) Granulocytes They stain a neutral pink when stained by H&E Nucleus divided into 2-5 lobes, cytoplasm with granules Neutrophils participate in defense against extracellular pathogens

Neutrophils The average half-life in circulation is about 12 hours Upon activation, they marginate (position adjacent to the endothelium) → rolling (selectins) → adhesion to endothelium (integrins) → diapedesis (integrins) → chemotaxis (movement toward sites of inflammation by cytoplasmic streaming in response to chemotaxins (IL-8, IFN-g, C5a) → binding to microbe

Neutrophils - phagocytosis Interaction with some surface molecules of microbes (PAMPs, lectin interactions, binding of TLR to some surface molecules of microorganisms) Opsonisation (= enhancement of binding of phagocytes to microbes) – Ig, complement system components, CRP, MBL

Neutrophils - phagocytosis Surrounding of microorganism → forming of vacuole (phagosome) → fusion with the lysosome → phagolysosome Phagosome formation depends on contractile proteins action

Neutrophils – intracellular destruction of microbes 1/ Oxygen independent systems substances that are contained in granules myeloperoxidase, lysozyme, alkaline phosphatase, lactoferrin → hydrolysis microbe’s cell wall components defensins → forming of channels in microbial cell membrane

Neutrophils – intracellular destruction of microbes 2/ Oxygen-dependent systems Respiratory burst NADPH oxidase system → production of reactive oxygen agents (hydrogen peroxide, superoxide anion, singlet oxygen, hydroxyl radicals) Disorder of this system in CGD

Neutrophils – intracellular destruction of microbes 2/ Oxygen-dependent systems Myeloperoxidase, in the presence of toxic oxygen metabolites, catalyzes peroxidation of surface molecules on microorganisms

Macrophages Intracellular destruction of microorganisms mainly by NO synthase (system stimulated by the action of IFN-g or TNF) Production of numerous substances: lysozyme, some components of the complement system, oxygen metabolites (H2O2, NO), cell function regulators (IL-1, IFN-a), arachidonic acid metabolites, endogenous pyrogens

Natural killer cells Granular lymphocytes, different from T- and B-lymphocytes Cytotoxicity to tumor cells and virally infected autologous cells (perforins) Play a role in defense against some bacterial, fungal and helminthic diseases Participate in reactions of antibody-dependent cell- mediated cytotoxicity (ADCC) They are not subject to MHC restriction (= NK-cells do not need to recognize MHC molecules in the target cells)

Natural killer cells They kill target cells by perforins (formation of channels, abnormal ion flux, depolarization, essential metabolite leakage, cell destruction) NK cells are protected against perforins by specialized cell membrane protein (protectin)

Interferons Proteins that induce antiviral activity in cells We can distinguish two types: a/ type I: IFN-a (macrophages and other cells) IFN-b (fibroblasts) b/ type II: IFN-g (T-lymphocytes)

Function of interferons Stimulation of cell production of antiviral proteins (protein kinase, oligonucleotide polymerase – interference with the translation of viral mRNA) Enhancement of T-cell activity Activation of macrophages Enhancement of NK cells cytotoxic action

Adaptive immune mechanisms 1/ Humoral generation of antibodies (Ig) – B cells (plasma cells) in majority of antigens, the cooperation with T helper cells is necessary 2/ Cell-mediated generation of antigen-specific T cells (helper, cytotoxic) antigen presentation is necessary

Adaptive immune mechanisms Antibodies → neutralization and opsonization (specific „adapter“) of microbes, complement system activation T cells → cytotoxic effects to microbes, help for B cells, macrophages activation, cytokines

Innate/adaptive immune mechanisms Innate (non-specific) immune system: prompt reaction x less effective, less directed Adaptive (specific) immune system: slower development of reaction x more effective, more directed, immunological memory Both systems cooperate (complement system is activated by IC, cytokines recruit other cells to the site of reaction, antigen presentation)