THE CELLS AND MOLECULES
OF THE IMMUNE SYSTEM
www.immunology.unideb.hu
Login: student
Password: download
Renata Laczik
•Why do you only get some infections like chicken pox only once?
•How do you generate a system able to recognise a broad array of pathogens
with high level of sensitivity and specificity using a finite amount of coding
DNA?
•Why do subsequent immune responses to a pathogen occur more rapidly
and at higher titers than previous immune responses?
•How does the immune system provide a high degree of sensitivity and
specifity to the broad array of pathogens without attacking self?
•Why are T cells and B cells effective against different pathogens and how do
T cells and B cells see antigens differently?
Combined severe immunodeficiency
THE ROLE OF THE IMMUNE SYSTEM
Differentiation b/w self and non-self structures
(Danger Model: altered/dangerous self,
dangerous/non-dangerous non-self)
- recognition of pathogen (antigen)
- presentation of pathogen (antigen)
- elimination of pathogen (effector function)
Native immunitiy
Adaptive immunity
- immediate reaction
- non-transmittable
- not specific
- no memory
- developes in several days
- transmittable
- antigen specific
- has memory
- humoral immunity
- cellular immunity
Some features of the innate immunity
Example for pathogen recognition, engulfment and digestion
pollen
leukocyte
red blood
cell
CELLS OF THE IMMUNE SYSTEM
The human body contains ca 1.000.000.000.000 (1012)
white blood cells
pollen
Red blood cell
White blood cells
PRODUCTION SITES OF IMMUNE CELLS
Embryo: yolk sac, liver, spleen
After birth: epiphysis, flat bones, red bone marrow
(sternum, ribs, vertebras, hip bone)
Constant and fast regeneration
FUNCTIONALLY DIFFERENT CELLS OF THE IMMUNE
SYSTEM
Resting lymphocyte
Plasma cell
Monocyte
Tissue dendritic cell
NK sejt
Mast cell
Macrophage
Lymph node dendritic cell
DIFFERENTIATION OF IMMUNE CELLS FROM
HEMATOPOIETIC STEM CELLS (HSC)
BONE MARROW
HSC - self renewal
HSC
MYELOID
PROGENITOR
LIYMPHOID
PROGENITOR
BLOOD
DC
monocyte mast cell neutrophil
BODY TISSUES
DC macrohage mast cell neutrophil
THYMUS
BLOOD
B-cell
NK-cell
T-cell
LYMPHOID TISSUES
B-cell
T-cell
Normal bone marrow smear taken from the posterior iliac crest
(middle aged person, about 50% cellularity)
Granulocytic
precursors
Erythroid islands
Megakaryocyte
Eosinophilic Basophilic
precursors
Plasma cell
Erythroid precursor
MONOCYTES
- origin: pluripotent cells of the bone marrow
myeloid progenitors
-size: 10-15um
- nucleus: bean-shaped
-localization: circulation
(out of circulation: macrophage)
MACROPHAGES
-
phagocytic cells
antigen presenting cells (APC)
main types (based on tissue localization):
a) microglia (brain)
b) Kuppfer-cells (liver)
c) histiocytes (connective tissue)
d) osteoclasts (bone)
e) alveolar macrophages (lung)
-function: in cellular and humoral immun-response
-Kupffer-cells represent 80% of the Mononuclear Phagocytic System (MPS)!
BASOPHIL 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
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
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
COMMON LYMPHOID PROGENITOR CELLS
B-limfocyte
(Bursa Fabricii)
T-limfocyte
(thymus)
maturation:
begins in bone marrow
continues in thymus
differentiation:
peripheral tissues
upon activation
plasma cells
effector T-cells
cytotoxic T-cell
helper T-cell
antigen recognition
via B-cell receptor
only via cell surface
MHC molecules
B-LIMFOCYTES
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
PLASMACELLS
-function: - antibody production
- humoral immunresponse
T- LIMFOCYTES
- 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 the peripheral (secunder)
lymphoid organs as TCR expressing T-lymphocytes
- csak az APC-k által, az MHC-n keresztül bemutatott antigéneket ismerik
fel
-types:
- T-helper (CD4+)
- T-citotoxic (CD8+)
- T-regulator (suppressor)
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”)
- native immunity
Lymphocyte populations in the human blood
T cells
35/26
Professional phagocytic cells
1. Dendritic cells
2. Macrophages
3. Neutrophil granulocytes
Professional antigen presenting cells (APCs)
1. Dendritic cells
2. Macrophages
3. B lymphocytes
Pathogens (viruses, bacteria) are processed by the APCs, the degradation products
(peptides) can be presented to T lymphocytes on MHC molecules
WHITE BLOOD CELLS IN THE SMEAR OF HUMAN
PERIPHERAL BLOOD
Neutrophil
Granulocyte
Eosinophil
Granulocyte
Monocyte
Neutrophil
Granulocyte
Lymphocyte
Basophil
Granulocyte
Lymphocyte
Full blood count
%
WHITE BLOOD CELLS
/ LEUKOCYTES
Cell number/mm3
4.8 – 10.8 x 109
Neutrophil
granulocytes
40 – 74
1.9 – 8 x 109
Eosinophil
granulocytes
0.1 – 5
0.01 – 0.6 x 109
Basophil
granulocytes
0.l – 1.5
0.01 – 0.2 x 109
19 – 41
0.9 – 4.4 x 109
3.4 – 9
0.16 – 0.9 x 109
Lymphocytes
Monocytes
RED BLOOD CELLS
erythrocytes
4.2 – 6.1 x 1012
PLATELETS
thrombocytes
150-400 x 109
LYMPHOID ORGANS
Primary lymphoid organs:
- Bone marrow
- Thymus
Secondary lymphoid organs:
- Lymph node
- Spleen
- Tonsils
- MALT (Mucosal Associated Lymphoid Tissue)
-GALT (Gut Associated Lymphoid Tissue)
- BALT (Bronchus Associated Lymphoid Tissue
Collaboration/communication of the leukocytes during an
immune response
APC
T
Direct
„communication”
Indirect
„communication”
Killer T cell
Helper T cell
Dendritic cell
Antigen
Alarm
B cell
Plasma cell
Antibody
Macrophage
MOLECULES
Cell surface molecules
markers (Cluster of Differentiation - CD)
receptors (BCR, TCR,
MHCI, MHCII, PRR, etc.)
costimulatory molecules
adhesion molecules
(integrins, selectins,
mucins, etc.)
Soluble molecules
cytokines
antibodies
complement components
metabolites
THE MOST IMPORTANT CELL SURFACE STRUCTURES OF
HUMAN LYMPHOCYTE POPULATIONS
The most important molecules in the interaction between extracellular matrix
and lymphocytes
lectin
domains
domains
cysteins
members of the Ig
superfamily
selectins
integrins
mucins
Members of the immunglobulin superfamily
Characterized by immunoglobulin (structural) units
FAMILY
FUNCTION
Integrins
- cell-cell and cell-extracellular matrix interaction
- migration of cells
- tissue organization
- inflammatory mechanisms eg. LFA-1
(Lymphocyte Function Associated Antigen)
Selectins
- transmigration of lymphocytes through the
vessel wall and settlement in tissues
- present on leucocytes and endothelial cells
- connect to carbohydrates on the cell surface
eg. L-selectin – directing lymphocyte traffic to
lymph nodes
mucins (addressins)
- glycosylated molecules
- transmigration of lymphocytes via HEV with the
aid of mucosal endothelial cells
eg. CD34, which binds to L-selectin over the
cell migration through HEVs of the lymph node
Proteoglycans
- important in the interaction between cells and
tissue enviroment
CYTOKINES
Characterized by origin and function:
- limphokines
- monokines
- interleukines (IL)
Have a role in:
- acute phasis reactions and inflammatory processes
- the maturation and development of immunocompetent cells
- Regulation of activation and differentiation of lymphocytes
cytokines
chemokines
monokines
interleukines
limphokines
Nomenclature is based mainly on the producing cell type
CYTOKINES
- The most important indirect cell-communaction molecules; „hormones”
of the immune system
- Effective in small concentration
- The presence cytokine-specific receptors
-autocrine, paracrine, endocrine
- synergistic
- antagonistic
- redundant
- subtypes
- cytokine receptor molecule families
chemokines:
enhance adhesion
chemotaxis (IL-8)
leukocyte activation
produced by macrophage, endothels, keratinocytes, fibroblasts,
smooth muscle, T-lymphocyts
Type I interferons
native immunity
protection agains virus, glycoproteins
IFNα
virus infected macrophes & and other leukocytes
IFNβ
fibroblasts
Type II interferons
IFNγ
Th1, CD8+ and NK cells
main role is the activation of macrophages
chemotactic factors
function together with the chemokines in
the inflammatory responses
EFFECTS of CYTOKINES
macrophage
makrofág
cytoxicity ­citotoxicitás
monokinek
monokines­ adhesion
molecules
adhéziós
molekulák ­
MHC
TCR TT-sejt
cell
autokrin IL-1 parakrin
prostaglandins
prosztaglandinok ­
láz fever
aluszékonyság
insomnia
fájdalomküszöb
weight loss ­
fogyás
pain
end okrin
bacterial
bakteriális
endotoxin
endotoxin
aktiváció
­
activation—
IL-2RIL2R
­
limfokinek ­
lymphokines
COMPLEMENT
enzyme cascade system in the plasma (enzymes are in an inactive form)
activation of the complement system
processes on the cell surface
generation of soluble factors
opsonin
anafilactic factors (C3a, C4a)
chemotactic factors (C5a)
factors facilitating the phagocytosis (C3b, iC3b, C4b, C5b)
METABOLITES
Influence the function of immune cells
ANTIBODIES – multifunctional proteins
produced by plasma cells differentiated from activated B lymphocytes
• antigen recognition and binding to antigens
• binding to cells
• involved in interactions between immune cells
• inducement of effector functions
• elimination of antigens
• activation of the complement system