ImmunologyHow the immune system works?

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Immunology

What is the strategy of the immune system?What type of cells / organs participate?Which genes determine its function?

Immunology studies the defensive mechanisms of our body, the cells, organs, molecular mechanisms that protect us

The immune system fights pathogenic organisms and inner enemies. Cellular and humoral mechanisms are working together with each other and with the neuro-endocrine system

The immune system can sense the microbiological environment of the organisms and is able to respond with proper answers

Certain mechanisms of the immune system can be detected even in microbes. Plants have highly developed immunityAdaptive immunity is present in vertebrates

The most basic task of the immune system is determination of „self”and „non-self”, „dangerous” and „not dangerous”

The immune system can detect and identify molecular patterns that proved to be dangerous during evolution (PAMPs: pathogen-associated molecular patterns). Response to the presence of these molecules is genetically encoded

The adaptive immune system of the vertebrates produces unique, recombinant receptors that can identify practically any molecule. Molecules identified by the adaptive immune system are called antigens (the patterns recognized are the epitopes

Antigens are not identical with pathogens: the immune system can recognize countless molecules in the organism itself, in the food, in symbionticmicroorganisms of the gut- (skin-, nasal-, vaginal-, etc.) flora

The response to the presence of an antigen can be vigorous attack, tolerance or ignorance

Tolerance is an active process, quite different than ignorance. Unimportant molecules can be recognized as antigens

Tasks of the immune system

In a multicellular organism „dangerous self or non-self” should not betolerated

To preserve genetic unity of the organism self and non-self cells must be distinguished

In a multicellular organisms very different cell types are present

Different cell types have the same genome, but express very different molecular patterns (proteins, carbohydrates, lipids, etc.)

Changes in the genome should be prevented: „dangerous self” (mutant cells, tumor cells, infected cells) should be killed

The immune system protects the genome against detrimental changes

Strategies of recognitionSize range: whatever is smaller than the smallest cells (red blood cells),

but larger than macromolecules is considered an enemy

Labeling of „self” cells: characteristic molecular patterns are used (sialicacid, ECM, MHC proteins, etc.)

Molecular patterns of „self” cellsExtracellular matrix (ECM), cell surface proteins, cell adhesion proteins

(CAM), carbohydrate moieties of glycoproteins

Carbohydrate side chains of proteins are produced in the endoplasmic reticulum and the Golgi. Patterns of glycosylation enzymes are characteristic for a given species/individual

Carbohydrate side chains of proteins play important rolesin cell-cell recognition (CAM) and identification of non-self

Proteins specifically recognizingcarbohydrate moieties arecalled lectins

Strategies of recognition

Size range: whatever is smaller than the smallest cells (red blood cells), but larger than macromolecules is considered an enemy

Labeling of „self” cells: characteristic molecular patterns are usedPAMP receptors to detect molecular patterns of pathogens,

signaling events triggered by non-self, protective mechanisms

bacteria: lipopolysaccharides, lipopeptides, flagella, fungi: polymannane, chitin, etc.worms, nematodes, filaria: chitinviruses: crystal-like molecular structuresplants: cellulose, chlorophyll

Strategies of recognition: toll-like receptors

Pattern recognition receptors have characteristic ectodomain withleucine-rich repeats

alpha helices

beta sheets

Strategies of recognition

Size range: whatever is smaller than the smallest cells (red blood cells), but larger than macromolecules is considered an enemy

Labeling of „self” cells: characteristic molecular patterns are usedPAMP receptors to detect molecular patterns of pathogens

Chemical systems: membrane attack complexes: complement, defensinsmechanisms preventing spread of infection: blood clottingkilling with free radicals: hemoglobin, hemocyanin

SOS signals of „self” cells: cytokines, chemokinesSOS signals of dying cells: ATP, IL-1, Hsp proteins

Strategies of recognition

Size range: whatever is smaller than the smallest cells (red blood cells), but larger than macromolecules is considered an enemy

Labeling of „self” cells: characteristic molecular patterns are usedPAMP receptors to detect molecular patterns of pathogensChemical systems: membrane attack complexesSOS signals

Changes in the level of certain „self” molecules (or local anoxia)

Innate and adaptive immunity

Innate immunityis borne with us,genetically determined (and very expensive)evolved during millions of yearseffective against „traditional” enemies,no memory, low specificityslow to respond to new challengesvery reliable

Adaptive immunityfast, flexible, highly specific,effective against all kind of enemies,unique recombinant genetic background, needs „education”, its destructive power must be controlled

The two system cooperates, synergizes with each other

Cell types of the immune system

Hemopoiesis:

the pluripotent stem cells (HSC) relatively few, asymmetrical cell divisions

progenitors: fast cell cycle, no G0continuous cell divisions

stroma cellscoordinate differentiation

programed cell death

Cell types of the innate immune system

The innate immune system is a combination of synergizing humoraldefenses and cellular mechanisms

Innate immunity is ancient, evolved during eons of time and has no memory

Two of the most important tasks of the innate immune system are the presentation of antigens of pathogenic organisms andcoordination of the defense mechanisms by cytokines

Cells of the immune system: phagocytes

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Monocytes, macrophages, polymorphonuclearneutrophils (PMN)

Phagocytic killing of invading microorganisms,

Clearing cellular debris,

Antigen presentation,

Production of cytokines, growth factors and chemokines(chemoattractive peptides)

The neutrophil granulocyte

The most abundant cell type of innate immunity is the neutrophyl granulocyteCytoplasm is full of granules

of cytotoxic compounds

Engulfs, kills and digests pathogens

O and N free radicals, HOClare produced

Killing of microorganismsfrequently leads to self destruction (pus)

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Cell types: neutrophil

• Polymorph neutrophil granulocytedigesting Staphylococcus aureus

• Reactive compounds (HOCl), free radicals (NO, O2-, ONOO−) killgerms as well as the cells –2.3. Gergely

Monocyte and macrophage

• Tissue macrophage clearing Staph. aureus cells

• PAMP receptors help to identify pathogenic cells

• Characteristic molecules of pathogens also activate macrophages (eg. pyrogens)

• Monocyte, Kupffer-cells, alveolar macrophage, histiocyte, microglia,mesangial cells, Langerhanscells, DC, etc.

Macrophage

Phagocytosed bacteria inthe macrophage

The primary goal is presentation of (foreign) antigens,not killing of microorganisms

Cell types of the immune system: dendritic cells

• Specialized cells: professional antigen presenting cells (APC)

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Langerhans cells

• Langerhans cells (stained brown) forming a network in the epidermis, areprofessional APCs

Engaging pathogensthey travel to lymph nodesto present antigens of theinvading microorganismto lymphocytes

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EosinophilEozinophil granulocytes have important role in the protective immunity

against eukaryotic parasitesbut also contribute to the inflammation that occurs in allergic disorders (IgE, IL-5, histamine)

They degranulate, releasing toxic substances, killing the parasite – but also cause tissue damage. Balance of positive and negative effect

Basophils, mast cells

Basophils secrete biologically active substances such as histamine, proteoglycans, or cyclooxigenase products.

Basophils are produced continually by stem cells in the bone marrow.

The function of basophils is not fully understood, but it is known that they are capable of ingesting foreign particles and produce heparin and histamine (chemicals which induce inflammation), and are often associated with asthma and allergies.

Related cells, known as mast cells initiate immune responses. Mast cells are tissue resident and contain histamine- and heparin-rich granules. They are also involved in wound healing and defense against pathogens

Natural killer cells (NK)

Natural killer cells develop from lymphoid progenitors

They kill cells without „self” label(no MHC expression)

Important role in the education of DCs

Decisive role in destruction of virus-infected- and tumor cells

Lymphocytes• T and B-lymphocytes belong to the

adaptive immune system,

• Unique genetic system: recombinase enzymes generate rearranged genes of antigen-recognizing receptors

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Organs of the immune system

Primary organs: Bone marrow, thymus

Secunder organs:

Lymph nodes, spleen

GALT: gut-associated lymphoid tissue,appendix, Peyer’s patches

MALT: mucosal-associated lymphoid tissue

BALT: bronchial-associated lymphoid tissue

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Bone marrow

• Stem cells of the bone marrow produce continuously dividing progenitors

• Stroma cells and cytokines direct differentiation of progenitor cells

• B cells mature in the bone marrow

• T cell progenitors migrate from the bone marrow into the thymus

The thymusDifferentiation and education of T cells takes place in the thymusMost of the T cells get killed in the thymus

The cortex contains T-cell precursors and epithelial cells, in the medullamature T cells, DCs, macrophages and medullar epithelial cells can be found

Lymph nodes

Lymph nodes are meeting places of B, T, DC and other immune cells. Lymph nodes, found all over the body trap for foreign particles.

Lymphocytes that have not encountered any antigen yet enter the node from the bloodstream, through specialized capillary venules.

Activated lymphocytes exit the lymph node through the efferent lymphatic vessel.

The lymphocytes continuously recirculatethe peripheral lymphoid organs and the state of the lymph nodes depends on infection.

Lymph nodesThe lymph node is surrounded by the capsule and inside the lymph node

the fibrous capsule forms trabeculae. The inner medulla is surrounded by the outer cortex. At the hilum the medulla comes in direct contact with the surface

Germinal centers (GC) where mature B lymphocytes rapidly proliferate, differentiate, mutate through somatic hypermutation and class switch during antibody responses.

Germinal centers are the mostimportant part of the B-cellhumoral immune response. They develop dynamically after the activation of B-cellsby T-dependent antigens.

The spleen

The spleen can be considered analogous to a large lymph node

The spleen removes antibody-coated bacteria and antibody-coated blood cells

B cells in its white pulp synthesize antibodies

Half of the monocyte population resideswithin the red pulp.

These monocytes move into injured tissue, turn intomacrophages and dendriticcells fighting pathogens, presenting antigens and promoting tissue healing

Marginal-zone B cells, serve special roles in theimmune system.

The Peyer’s patchesAggregated lymphoid nodules orPeyer's patches found in the lowestportion of the small intestine ileumPeyer’s patches are lymphoid follicles, similar to lymph nodesPeyer's patches participate in theimmune surveillance of the intestinallumen Pathogenic microorganisms and other antigens entering the intestinaltract encounter macrophages, DCs, B and T cells found in Peyer's patches (and other gut-associated lymphoidtissue, GALT)Specialized cells called microfold cells(M cells) sample antigen directly fromthe lumen and deliver it to antigen-presenting cells, APC

IgA

M-cells

germ center