Download Physiology of the Blood III. White Blood Cells and the Immune

Physiology of the Blood III.
White Blood Cells and the
Immune System 2.
Prof. Szabolcs Kéri
University of Szeged, Faculty of Medicine,
Department of Physiology
2016
Virus infected cell,
Tumor cell
CD8 T [killer] cell - MHC-I+antigen
NK cell
CELLULAR IMMUNITY
Bacteria
CD4 T [helper] – MHC-II+antigen
B cell: antibody
HUMORAL IMMUNITY
Adaptive immunity 1.
Antigen presentation in the membrane:
MHC (major histocompatibility complex) – a protein joined to the
antigen for cell surface display (HLA – human leukocyte antigen)
MHC-I
- every cell contains in membrane
- high degree of variety, individual differences (marker of „my cells”)
- part of it: TAP/tapasin antigen processing molecule
- cytotoxic T-cells recognize MHC-I (virus infected cell, tumor cell, tissue
from another non-compatible individual)
MHC- II
- only in the membrane of immune cells (antigen presenting cells)
- join to antigen-fragments digested in the lysosomes (e.g. bacteria)
- helper T-cells recognize MHC-II
The role of MHC-I in the recognition of self-cells
The „Missing Self” hypothesis
Adaptive immunity 2.
Helper T-cell (TH)
- CD4 membrane marker
- its receptor recognizes MHC-II + antigen complex
- type 1: facilitation of further phagocytosis
- type 2: facilitation of B-cells – specific production of antibodies
Cytotoxic T-cell (T-killer, T-effector)
- CD8 membrane marker
- recognizes MHC-I
- virus/tumor cell (apoptosis, perforation of the membrane)
- NK-cell: cytotoxic without antigen-specificity (part of innate immunity)
CD = Cluster of Differentiation
Adaptive immunity 3.
Memory cell
- CD8/CD4 or B-cell
- stores the memory of antigens for years, fast activation and division
in the case of new exposition
Regulatory T-cell (suppressor T-cell)
- immuntolerance: active inhibition of response in the case of
the antigens of self-tissue and tolerated (non-harmful) others
- central: selection of autoreactive cells in the thymus
- peripheral: demarcation (e.g. brain, eye, joints), inhibitory cytokines (TGF),
negative co-stimulation (CD molecules)
γδ T-cell
- receptor consists of γδ subunits instead of the common αβ
- intraepithelial lymphocyte in the mucosa
- recognizing whole proteins without MHC
Interim summary 1. Framework of the
specific immune response, cellular
immunity
• Antigen presenting cells – antigen part with MHCII (e.g., dendritic cell)
• T[helper] – activation of other T és B cells
• T[killer] – virus and tumor cell (cellular immunity,
MHC-I)
• MHC-I: discrimination of self and alien cells
• Immuntolerance (physical separation, inhibiting
receptors and cytokines, suppressor T-cells)
Adaptive immunity 4.
B-cells
- transformed to plasma cells producing antibodies
- antigen presentation
- B-cell receptor = antibody inserted in the B-cell
membrane
Antibodies (immunoglobulins, Ig):
IgG: most common, binds phagocytes (opsonization), passes placenta
IgM: ancient, initial synthesis
IgA: in mucosa-secreted fluid
IgE: cytophil antibody, binds to basophils and mast cells
IgD: B-cell receptor before antigen exposition
The structure of the antibody
Antigen binding
Variable region
Complement binding
Fc receptor binding part
(e.g. macrophages)
L – light chain
H – heavy chain
Humoral (antibody dependent) immunity
The special role of the NK-cells: „cellular - humoral hybrid”
ADCC – antibody-dependent celullar cytotoxicity
Ag – antigen
Ab –antibody
FcR – Fc-receptor
Fas (CD95) – apoptosis inducing „death” receptor-ligand complex
Granzyme/Perforin – factors for cytolysis
Interim summary 2. Specific immune
response: humoral immunity
• B cell – transformation to plasma cells,
antibody production
• Antibody structure and groups: „Y”, Fab,
Fc regions, complement binding, light
and heavy chain
• „MEGAD”
• ADCC – role of antibodies in cytotoxicity
Mediator substances of the immune response
and inflammation
1. CYTOKINES
2. ARACHIDONIC ACID DERIVATES
3. COMPLEMENT
4. Acute phase proteins (produced by liver during inflammation
and tissue damage) - C-reactive protein, serum amyloid A,
procalcitonin – opsonization, precipitation, immune cell activation
5. Kinin-kallikrein system (bradykinin) (blood pressure, blood
coagulation, pain, local inflammation)
INFLAMMATION:
„Rubor, tumor cum calore et dolore et functio laesa”
(Red, swollen, warm, pain, impaired function)
Matter (pus, purulent): leukocytes + tissue debris
Cytokines 1.
- Communication and functioning of leukocytes: division, differentiation,
chemotaxis, antibody production, cytotoxicity
- System-level effects: fever, increased metabolism, nervous system,
cytokine-storm ↔ chronic inflammation, autoimmunity
1. INTERLEUKINS (IL)
2. INTERFERONS (INF) (antiviral, treatment of tumors & autoimmune diseases)
3. TUMOR NECROSIS FACTOR (TNF)
4. TRANSFORMING GROWTH FACTOR (TGF) (tumors, tissue regeneration)
5. COLONY-STIMULATING FACTORS (CSF) (bone marrow, cell division)
6. ADIPOKINES (produced by visceral fat!)
Cytokines 2.
1. Macrophages „first signal”: IL-1, IL-6, TNFα
2. Cellular immunity: INFγ, TGFβ
3. Antibody production: IL-4, -10, -13 (IL-14 inhibits)
4. Chemotaxis: IL-8
5. TH-stimulation: IL-2
6. Granulocyte-activation: IL-5 (eosinophil), IL-3 (mast cell)
Arachidonic acid derivates
ARACHIDONIC ACID: long-chain unsaturated fatty acid of
the plasma membrane mobilized by phospholipase A2
Cyclooxygenase (COX)-pathway:
- prostaglandins (PGD2, -E2, -F2)
- prostacyclin (from PGI2)
- thromboxane (TXA2)
Lipoxygenase-pathway:
- leukotrienes (LTC4, -D4, -E4, -F4)
Endogenous cannabinoids (e.g. anandamide [arachidonoylethanolamine] as an
immune system modulator)
NSAID (non-steroid antiinflammatory drugs): aspirin
- COX1: prostaglandins protecting the mucosa of the stomach
- COX2: inflammatory derivates
- Selective COX2-inhibition (e.g. Vioxx) – thrombosis: connection between blood coagulation
and inflammation
- Paracetamol (acetaminophen), a painkiller and anti-fever drug, may enhances
anandamide level
The complement system
A proteolytic cascade in the
plasma, produced by the liver
in precursor forms
Activation:
Classic: antibodies
Alternative: antigens (Toll-like
CRP = C-reactive protein
receptors)
lectins (=specific sugar
binding proteins attaching to
membranes)
Function:
- Cytolysis (membrane pore –
C5-9)
- Chemotaxis (C5a fragment)
- Opsonization (C3b, C4b)
- Changing the molecular
structure of viruses
MAC = membrane
attack complex
Interim summary 3. Substances
regulating the immune system
• Cytokines: IL, TNF, INF
• Arachidonic acid: prostaglandins and
leukotrienes (inflammatory reaction, NSAID)
• Acute phase proteins: liver’s reaction to
inflammation and tissue damage
• Complement system: chemotaxis,
opsonization, cytolysis – reaction dependent
and independent of antibodies