Biochemistry of Immune System
immunity
the defense mechanisms that allow the organism to be resistant to foreign
substances, e.g. infectious agents
innate immunity
the first response, no antigen-specific recognition mechanisms
(complement system, acute phase proteins, phagocytizing cells)
adaptive immunity
antigen dependent immune response, antigen-specific recognition mechanisms
 regulation of innate defense mechanisms: they change the antigen structure
in such a way, that innate immunity is enabled to eliminate the antigen
(antibodies, lymphocytes, macrophages)
antigens
foreign substances that the immune system recognizes
Mechanical defense mechanisms
- barriers (epithelial cells of the skin and the mucous coat of the mucous membranes)
- extensively glycosylated proteins (mucoproteins), secretory IgA, lysozyme, lactoferrin, proteinase inhibitors
Complement system
- the most important nonspecific mechanisms
- group of about 20 plasma proteins (mainly C1 - C9) and some cell receptors
- synthesis: liver, monocytes, macrophages (at the site of inflammation)
- secreted in an inactive state
- central component: C3  activated by C3-convertases: alternative, classical or lectin pathway
(C3 is a part of 2-globulin electrophoretic fraction, blood serum concentration: 0.45 - 0.83 g/L);
concentration of C4 is laboratory established too
effects of complement:
1) the initiation of inflammation
2) the facilitation of antigen elimination by phagocytosis and cellular lysis
major effector molecules:
C3a, C5a, C4a
anaphylatoxins  cause release of histamine from mast cells
C5a, C3a, C567
chemotactic effect  attract macrophages to the inflammatory region
C3b
the most important opsonin  it binds to specific receptor of macrophages and
granulocytes to facilitate phagocytosis and proteolytic degradation of infectious
pathogens
C5b - 9
membrane attack complex  osmotic lysis of target cells
(transmembranous channel)
C1s, C3d-kallikrein cause release of neutrophilic granulocytes from the storage pool of bone marrow,
C1s activates platelets, the coagulation system
C4b, C3b
solubilize immune complexes
Acute phase proteins (Acute phase reactants)
- plasma concentration increased in response to body´s injury (inflammation, myocardial infarction,
malignancy, trauma, ...)
- diverse functions: bind to bacterial walls
activate complement
stimulate phagocytosis
- increase within 24 hours of injury in response to humoral mediators (cytokines produced by tissue
macrophages, monocytes, endothelial cells, e.g. IL-1, IL-6, TNF-)
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C - reactive protein (CRP)
- important indicator of acute or chronic inflammation
- the most stimulus to its production: bacterial infection
- rapid to response (6 hours, up to 1000 times elevated blood serum concentration; physiological
concentration is about 1.3 mg/L)
- synthesis: liver (stimulus: IL-6)
- ability to bind wide range of endogenous and exogenous substances  opsonisation
- recognizes damaged cells and their products which may be toxic or allergic
1 - antitrypsin (1-AT, 1-Pi, 1-proteinase inhibitor)
- inhibitor of proteolytic enzymes derived from leukocytes, bacteria, endogenous production (e.g., elastase)
- synthesis: hepatocytes, alveolar macrophages and monocytes
1 - antichymotrypsin
- inhibitor of proteolytic enzymes
haptoglobin
- 2 - globulin (electrophoretic fraction), synthesized in the liver
- bind free hemoglobin to form complexes that are metabolized in the reticuloendothelial system
fibrinogen
- involved in a blood clotting (Factor I)
- synthesis: liver
ceruloplasmin
- 2 - globulin
- synthesis mostly in the liver
- transport of Cu in plasma, ferroxidase activity: Fe2+  Fe3+
- regulation of transport, availability, and redox potential of iron
Compensation of the elevated protein concentration during the inflammation (proteins mentioned above and
immunoglobulins): reduction in the concentration of negative acute phase proteins, e.g. albumin, transferrin
Immunoglobulins (Ig)
- glycoproteins with antibody activity
- general structure: 2 heavy + 2 light chains (specific domains  function)
- 5 classes according to the type of the heavy chain: IgG, IgA, IgM, IgD, IgE
-  - globulins (electrophoretic fraction)
- synthesis: plasmocytes
IgG
4 subclasses, 75 % of all serum Ig, serum concentration: 7 - 16 g/L, recurrent immunization,
T1/2 = 20 days, the least Ig, cross placenta
IgM
2 subclasses, the first immunoglobulin response, pentamer, the highest molecular mass, bind
complement, free (0,4 - 2,3 g/L) or bound to the B-lymphocyte surface
IgA
2 subclasses, monomer (serum) or dimer (serum, secretions), high antiviral activity;
serum: 0,7 - 4 g/L, immunity for newborns: part of the mother´s milk
IgD
surface of B-lymphocytes
IgE
antiallergen activity (allergic reactions)
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Granulocyte defense functions
polymorphonuclear granulocytes (PMN)
neutrophilic PMN
phagocytosis, the most important during an acute inflammation
eosinophilic PMN
phagocytosis of immune complexes, allergic reactions; produce the alkaline
protein toxic for parasites (ECP = eosinophil cationic protein)
basophilic PMN
allergic reactions, similar to mast cells
mast cells
release eicosanoids and histamine  increase of vascular permeability
Metabolism of neutrophil granulocytes
- low number of mitochondria
- active glycolysis and hexose monophosphate pathway
- lysosomes with proteolytic enzymes and the other hydrolases (e.g. lysozyme)
- unique enzymes: NADPH - oxidase
myeloperoxidase (MPO)
- ability to migrate towards an infected site, absorb bacteria and destroy them intracellularly
(integrins, chemotaxis = target-oriented movement, opsonized bacteria = with „plasma proteins coat“,
phagolysosome)
activation:
G - proteins  phospholipase C  IP3 ( elevation of Ca2+ concentration)
DAG (activation of proteinkinases)
 increase of the cellular oxygen demand and the glucose consumption  OXIDATIVE BURST
 production of reactive oxygen species (ROS) into the phagolysosome:
 2 O2- + NADP+ + H+
NADPH - oxidase (membrane)
2 O2 + NADPH
dismutation of 2 O2- (no enzyme)
O2- + O2- +
2 H+  H2O2 + O2
superoxide dismutase (cytosole)
O2- + O2- +
2 H+  H2O2 + O2
myeloperoxidase
H2O2 + Cl- + H+
 HClO + H2O ( chloramines)
↓
toxic for many bacteria
+ dephensines (peptides)
+ cathepsine G (protein) and the other hydrolytic enzymes (e.g. elastase, lysozyme)
 killing of bacteria within phagolysosomes
Important factor: ratio proteases / antiproteases concentration, high amount of ROS  damage of
surrounding tissue  inflammation
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