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2. THE CELLS AND MOLECULES
OF THE IMMUNE SYSTEM

3. WHAT IS THE FUNCTION OF THE
IMMUNE SYSTEM??
How does it need to function?
Is there room for failure?
Immunodeficiencies!!!
What about speed?
What about specificity?
What about flexibility?
What about functional overlap?
Many different germs are controlled efficiently.

4. Immunitas = exemption, protection
Protection from / against what?
Self or non-self substances?
(What about the useful bacteria living together with us and what about tumors in this modell?)
„Danger model”:
(Matzinger P., The danger model: a renewed sense of self. Science Apr 12;296(5566):301-5.)
harmful self / harmless self
harmful non-self / harmless non-self factors!
DANGER SIGNAL / NO DANGER SIGNAL
obligate pathogen
facultative pathogen (Staphylococcus aureus)

5. Vaccination is a powerful weapon against pathogens
and prevent epidemics
Smallpox virus was declerad eradicated
In 1979 by WHO
Upper panel: smallpox vaccination was started in In 1979, after 3 years in which no case of smallpox was recorded, the World Health Organization announced that the virus had been eradicated. Since then the proportion of the human population that has been vaccinated against smallpox, or has acquired immunity from an infection, has steadily decreased. The result is that the human population has become increasingly vulnerable should the virus emerge again, either naturally or as a deliberate act of human malevolence. Lower panel: photograph of a child with smallpox and his immune mother. The distinctive rash of smallpox appears about 2 weeks after exposure to the virus. Photograph courtesy of the World Health Organization.

6. THE TWO ARMS OF THE IMMUNE SYSTEM
Differentiation between harmless and harmful impacts
DETECTION OF STRESS AND DANGER SIGNALS
INNATE IMMUNITY
Differentiation between self and non-self structures
Antigen-specific recognition
ADAPTIVE IMMUNITY
Neutralization and elimination of foreign and harmful structures
EXECUTIVE FUNCTIONS
COORDINATED AND REGULATED ACTIONS
INNATE IMMUNITY
immediate reaction
non-transmittable
not antigen-specific
no memory
ADAPTIVE IMMUNITY
developes in several days
transmittable
specific
has memory
communication
Humoral immunity
Cellular immunity

7. Recognition of pathogens by the innate arm of the immune system.
Almost all components of the immune system contribute to mechanisms for either recognizing pathogens or destroying pathogens, or to mechanisms for communicating between these two activities. This is illustrated here by a fundamental process used to get rid of pathogens. Serum proteins of the complement system (turquoise) are activated in the presence of a pathogen (red) to form a covalent bond between a fragment of complement protein and the pathogen. The attached piece of complement marks the pathogen as dangerous. The soluble complement fragment summons a phagocytic white blood cell to the site of complement activation. This effector cell has a surface receptor that binds to the complement fragment attached to the pathogen. The receptor and its bound ligand are taken up into the cell by phagocytosis, which delivers the pathogen to an intracellular vesicle called a phagosome, where it is destroyed. A phagocyte is a cell that eats, "phago" being derived from the Greek word for eat.

8. The innate and the aquired arm of the immune system works hand-in-hand to eliminate germs
IDE JON A MOZI!!!!
IDE JON A MOZI
An immune response involves events that unfold both locally, at the site of an infection, and at more distant sites, such as nearby lymph nodes. We can see the integration of the different parts of the immune response if we follow the course of a typical infection. Most pathogens are kept outside of the body by epithelial barriers, such as the epidermis, and are crossed only when there is an injury or tissue damage. After an injury, bacteria cross the epidermis and establish an infection in the underlying tissue. Phagocytic cells in the tissues, such as macrophages and neutrophils, engulf the pathogen. Dendritic cells are also phagocytic, and are activated by binding pathogens to leave the site of infection and migrate to a lymph node. The migrating dendritic cells enter the lymphatic vessels and are collected in a draining lymph node. In the lymph node, T cells are activated by antigen presented by the dendritic cells, and in turn activate B cells to secrete antibody. Effector T cells and antibody molecules return to the circulation. They leave the circulation again at the site of infection, where inflammatory mediators have induced changes in the blood vessel endothelium. CD4 T cells activate macrophages to become more cytotoxic, while antibody recruits complement to lyse bacteria directly and to opsonize them, enhancing their uptake by phagocytes. In the case of a viral infection, activated CD8 T cells would kill any infected cells present.

9. Pathogens win the battle in the absence
of either the innate or the adaptive arm of immunity

10. Innate immune mechanisms establish a state of inflammation at sites of infection.
Illustrated here are the events following an abrasion of the skin. Bacteria invade the underlying connective tissue and stimulate the innate immune response.
How do innate cells recognize bacteria and various other pathogens?
Is the reaction specific?

11. Recognition of lipopolysaccharide by Toll-like
receptor 4 (TLR4)
In the initial stages of an immune response, the innate immune system recognizes the presence of pathogens and provides the first line of defense. Dendritic cells, which are circulating through the tissues, have the ability to recognize the presence of pathogen associated molecular patterns or PAMPS. PAMPS are conserved features of pathogens, such as the lipopolysaccharides or LPS, which are components of the cell membranes of all gram-negative bacteria. Dendritic cells have the ability to recognize PAMPS through the expression of a family of Toll-like receptors or TLRs. In the case of LPS, it is recognized by one member of the TLR family, TLR-4, which is expressed on the surface of the dendritic cell. LPS is transported by the soluble LPS-binding protein, LBP, to the surface of the dendritic cell, and deposited on the cell surface protein CD14. The presence of LPS is detected by TLR-4 through its interaction and recognition of the LPS bound to CD14. The signal delivered by the TLR initiates maturation of the dendritic cell. The dendritic cell can now migrate to regional lymph nodes and activate the acquired immune response.

12. CONSTANT REGENERATION
THE SITES OF IMMUNE CELL PRODUCTION DURING
DEVELOPMENT
embryo: yolk sac, liver, spleen
after birth: - epiphysis
- flat bones – red bone marrow
(sternum, ribs, vertebras, hip bone)
CONSTANT REGENERATION
FAST REGENERATION
INTENSE ADAPTATION

13. Immunocompetent cells derive from a common hematopoietic stem cell

14. FUNCTIONALLY DIFFERENT CELLS OF THE IMMUNE SYSTEM
Resting lymphocyte
NK cell
Plasma cell
Mast cell
Monocyte
Macrophage
Lymph node dendritic cell
Tissue dendritic cell

15. MONOCYTES MACROPHAGES
origin: pluripotent cells of the bone marrow
myeloid progenitors
size: 10-15um
- nucleus: bean-shaped
localization: circulation
out of circulation: macrophage
TISSUE - VENTRICLE
MACROPHAGES
phagocytic cells
antigen presenting cells (APC)
main types (based on tissue localization):
microglia (brain)
Kuppfer-cells (liver)
histiocytes (connective tissue)
osteoclasts (bone)
alveolar macrophages (lung)
- function: in cellular and humoral immun response

16. BASOPHIL GRANULOCYTES NEUTROPHIL GRANULOCYTES EOSINOPHIL GRANULOCYTES
1% of circulating leukocytes
large granules in the cytoplasm
nucleus with 2 lobes
mast cells, histamin, allergic reactions
high affinity IgE receptors
against parasites
NEUTROPHIL GRANULOCYTES
highest number in blood (68% of circulationg leukocytes,
99% of circulating granulocytes)
phagocyting cells
- does not present in healthy tissues
tissue damage, migration, elimination of pathogens
(enzymes, reactive oxygen intermediers)
main participants in inflammatory processes
EOSINOPHIL GRANULOCYTES
agains parasites
2-3% of leukocytes
allergic reactions

17. MAST CELLS origin: pluripotent cells of the bone marrow
myeloid progenitors
localization: absent from circulation
differentiate in tissues
especially around small vessels
function: - upon activation they regulate the permeability of the vessels with
their secreted molecules
- native and adaptive immunity
- allergic reactions (cell surface FceRI receptors)
- main types: a) mucosal
b) connective tissue

18. DENDRITIC CELLS origin: myeloid or lymphoid progenitors
localization: the immatured dendritic cell migrates from the circulation into the tissues and upon pathogen uptake it differentiates to matures dendritic cell and migrates to the draining lymph nodes
antigen presenting cells (APC)
types :
a) myeloid DCs: - Langerhans cells (mucosa, skin)
- intersticial DCs (liver, spleen, etc.)
b) lymphoid DCs: - thymic DCs
- plasmacytoid DCs (pDC)
Follicular DCs: stroma cells of the centrum germinativum of lymph nodes

19. COMMON LYMPHOID PROGENITOR CELLS
B lymphocyte T lymphocyte
(Bursa fabricii) (thymus)
maturation:
begins in bone marrow
continues in bone marrow continues in thymus
differentiation:
peripheral tissues
upon activation
plasma cells effector T cells cytotoxic T cell
helper T cell
antigen recognition
only via cell surface
MHC molecules

20. B LYMPHOCYTES PLASMA CELLS
origin: pluripotent cells of the bone marrow
lymphoid progenitors
maturation: bursa equivalent tissues
(embrionic liver, later bone marrow)
localization: takes 5-10% of the circulating lymphocytes; migrate from the bone marrow to the secondary lymphatic organs thorugh the circulation
antigen presenting cells (APC)
activation: with antigens, via interaction with macrophages or
T lymphocytes, lymphokines, cytokines
upon activation they differentiate to plasma cells or memory B cells
PLASMA CELLS
function: - antibody production
- humoral immun response

21. T LYMPHOCYTES - origin: pluripotent cells of the bone marrow
lymphoid progenitors
- maturation: thymus
localization: in the thymus the thymocytes mature into
immunocompetent T cells and they enter to the peripheral (secunder)
lymphoid organs as TCR expressing T lymphocytes
antigen recognition only in MHC molecules on the surface of APCs
types:
- T helper (CD4+)
- T cytotoxic (CD8+)
- T regulator (suppressor)

22. NK CELLS (natural killer)
- origin: pluripotent cells of the bone marrow
lymphoid progenitors
- bigger than lymphocytes
several granules in their cytoplasm
has no antigen binding receptors („null cells”)
participants of native immunity

23. Professional phagocytic cells Professional antigen presenting cells
macrophages
neutrophyl granulocytes
dendrtitic cells
the phagocytosed cells or molecules may modify
the functions of the cell
phagocytosis followed by enzymatic degradation
Professional antigen presenting cells
macrophages
B lymphocytes
dendrtitic cells
they express MHC molecules
the protein degradation products (peptides) can be presented
to T lymphocytes by MHC molecules

24. WHITE BLOOD CELLS IN THE SMEAR OF HUMAN PERIPHERAL BLOOD
eosinophil
granulocyte
neutrophil
granulocyte
MONOCYTE
neutrophil
granulocyte
LYMPHOCYTE
LYMPHOCYTE
basophil
granulocyte

25. DISTRIBUTION OF BLOOD CELLS AND LYMPHOCYTE SUBTYPES
Percentage
Cell number/mm3
WHITE BLOOD CELLS
leukocytes
4.8 – 10.8 x 109
neutrophil
granulocytes
40 – 74
1.9 – 8 x 109
eosinophil
0.1 – 5
0.01 – 0.6 x 109
basophil
0.l – 1.5
0.01 – 0.2 x 109
lymphocytes
19 – 41
0.9 – 4.4 x 109
monocytes
3.4 – 9
0.16 – 0.9 x 109
RED BLOOD CELLS
erithrocytes
4.2 – 6.1 x 1012
PLATELETS
thrombocytes
x 109

26. LYMPHOID ORGANS Primer lymphoid organs: Secunder lymphoid organs:
- bone marrow
- thymus
Secunder lymphoid organs:
- lymph node
- spleen
- tonsillas
- MALT (Mucosal Associated
Lymphoid Tissue)
-GALT (Gut Associated
- BALT (Bronchus Associated
Lymphoid Tissue

27. MOLECULES OF THE IMMUNE SYSTEM
Cell surface molecules:
markers (CD)
receptors (BCR, TCR, MHCI, MHCII, PRR, etc.)
costimulatory molecules
adhesion molecules (integrins, selectins, mucins, etc.)
Soluble molecules:
cytokines
antibodies
complements
metabolites

28. The main types of cell surface molecules participating in
antigen recognition and
the interaction between dendritic cells
and T cells

29. In plasma and other fluids
SOLUBLE MOLECULES
In plasma and other fluids
plasma: 90% H2O
10% dry material: 90% organic material
10% inorganic material
organic material : carbohydrate (glucose)
lipid (ckolesterol, triglicerid, phospholipid, lecitin, fat)
protein (globulin, albumin, fibrinoggn)
glycoprotein
hormon (gonadotropin, erytropoetin, trombopoietin)
amino acids
vitamins
Minerals: in ionic, water-soluble forms
BIOACTIVE MOLECULES, THEY INFLUENCE THE ACTIVITY AND FUNCTION OF THE IMMUNE SYSTEM

30. ROUGH CATEGORIES OF HORMONES
hormons
cytokines
interleukines
chemokines
monokines
lymphokines
interferons