1) Cells of the innate immune system such as neutrophils, macrophages, and dendritic cells provide the first line of defense against pathogens. These cells recognize pathogens through pattern recognition receptors and respond through phagocytosis or release of inflammatory signals. 2) Neutrophils are recruited to sites of infection where they phagocytose and kill microbes using mechanisms like release of antimicrobial proteins or formation of neutrophil extracellular traps. Macrophages reside in tissues and remove cellular debris and pathogens through phagocytosis. 3) The commensal microbiota colonizing mucosal surfaces provides a barrier against pathogen invasion and helps develop the adaptive immune system through interactions with mucosal tissues like Peyer's patches. The innate

1. Department of immunology,
microbiology and virology
Radaeva Olga Alexandrovna
Docent at Department of immunology,
microbiology and virology.
Allergist - immunologist
Deputy Director for extracurricular
activities

2. «Anatomical and chemical barriers.
Communication between host
immune system and commensal
microbiota.
Cells of the innate immunity.
Phagocytosis»

3. Immunity –
is a way of protection against
genetically foreign substances
(simple example: microorganism)
that damage the organism. The
main purpose is to maintain
homeostasis.

4. Function of immunity
Protection
of "non-self"
Tolerance
of "non-self"
this not damages
protection of infectious
diseases
- the fetus in the uterus,
- the сommensal microbiota
Immunity controls homeostasis
if damages

5. Types of immunity:
1. Innate immunity 2. Adaptive immunity

6. Innate immunity not only provides the early defense against infections
but also instructs the adaptive immune system to respond to different
microbes in ways that are effective for combating these microbes.
Conversely, the adaptive immune response often uses mechanisms of innate
immunity to eradicate infections. Thus, a constant bidirectional cross-talk
occurs between innate immunity and adaptive immunity.

7. Mechanisms of innate immunity:
1/ Anatomical and chemical barriers (the
skin and mucous membranes, body
temperature, pH and various body
secretions).
2/ Commensal microbiota (nonpathogenic
bacteria colonize epithelial surfaces).
3/ Cellular elements (neutrophils, eosinophils,
basophils, mast cells, monocytes/
macrophages, dendritic cells, NK cells, and
NK T cells).
4/Humoral elements (the complement system,
the interferon system, LPS binding protein,

8. Anatomical and chemical mechanisms of
innate immunity :
1. The skin and mucous membranes
(mechanical barrier).
2. PH and various body secretions.
3. Body temperature.

9. Anatomic and physiologic barriers
provide the crucial first line of defense
against pathogens.
The Skin. Some of the reasons skin is a
barrier to infection include:
- the outer layer is relatively dry and is dead,
acting as a mechanical barrier
- secretions from sweat glands inhibit
growth (high in salt; contains lysozyme
which breaks down cell walls by attacking
peptidoglycan's sugar links, antimicrobial
peptides)
- sebum (sē-bum) from oil glands is a
chemical barrier, coats skin/hair oil, sebum
lowers the pH between 4-6.

10. Mucous Membranes
- Mucous Membranes line the body cavities that
are open to the exterior and act as a mechanical
barrier to infection.
- They have secretions (mucus, antimicrobial
peptides) that act as nonspecific mechanical and
chemical barriers to infection.
- Certain mucous membranes have specialized
defenses -trachea have cilia.
- They have two layers, an outer epithelium and
an inner connective tissue layer.
- The thin living epithelial layer provides a less
efficient barrier than the skin, with the respiratory
and reproductive systems being common entry
sites for pathogens.

11. • nose hairs that filter out dust and microbes
• mucous that traps many microbes
(mechanical barrier)
• mucous that contains antimicrobial
peptides and antibodies (chemical
barriers)
• the ciliary escalator (ciliated cells which
propel microbes up toward the
mouth)when you cough
• gastric juice kills many bacteria and
inactivates many toxins (chemical barrier).
The Respiratory System and
its Defenses:

12. Other Defenses and Barriers:
• A mechanical barrier to infection includes the flow of
urine through the urinary system which sweeps bacteria
out.
• Vaginal secretions are both mechanical & chemical
barriers.
• Blood contains transferrins, proteins which bind iron. By
reducing the amount of available iron these chemical
barriers inhibit the growth of bacteria in the blood.
• Tears, saliva, and nasal mucus contain lysosyme (an
enzyme that degrades peptidoglycan).
• Tears are a mechanical barrier that wash the eyes upon
blinking.
• Gastric juices contain digestive enzymes and acids.

13. Commensal microbiota
.

14. Commensal microbiota.
• These nonpathogenic microorganisms are found
on the skin, in the mouth and in the reproductive
and gastrointestinal tract.
• The gastrointestinal tract contains many billions
of bacteria that have a symbiotic relationship.
• Imbalance of the commensal microbiota, called
dysbiosis.
• The relationship between the host immune
system and the commensal microbiota is highly
complex because these microbes possess many
of the same traits as pathogenic microorganisms.

15. Hence, the immune system must coexist with
commensal microbiota and maintain a state
of tolerance to self and innocuous
environmental, yet be able to vigorously
repel invasion by a wide spectrum of
pathogens.

16. The presence of a
functional barrier, with
normal amounts of PRRs
with mucus, and secreted
IgA, promotes intestinal
homeostasis with the
microbiota. The microbiota
is segregated away from
the immunity, and the
intestinal immune system
directs a largely tolerant
response to the resident
commensals. A breach in
the epithelial barrier by the
bacterial agents, pathogens
and other human diseases
(cholecystitis, pancreatitis,
endocrine pathology) can
lead to contact receptors
and microbiota. Immunity
attacks and kills
сommensal microbiota.
Functional barrier and barrier defect
(the intestines)

17. Commensal microbiota
Normal microbiota does not
damage and does not activate
the epithelium (only PAMPs)).
Normal microbiota has no
contact with the pattern
recognition receptors
The epithelium synthesizes
anti-inflammatory cytokines
Toleration
Pathogens
Pathogens damage and
activate the epithelium
(PAMPs + DAMPs)
Pathogens have contact with
the pattern recognition
receptors
The epithelium synthesizes
inflammatory cytokines
Elimination
The more important issue of how the immune system can
distinguish between beneficial and pathogenic microbes is still
largely a mystery. Innate barriers ensure a tolerant response to
the microbiota.

18. The Microbiota serves many functions.
• Competition for adherence to the epithelia and mucosal
surfaces as well as acidification of the microenvironment to
prevent attachment pathogens
• Consuming nutrients that would otherwise be available to
pathogens.
• Secretion of anti-microbial peptides
• Development of gut-associated lymphoid tissues (GALT)
• Normal flora of the intestines improve our overall health by
producing several types of vitamins.
While epithelial cells are often viewed as the first line of defense against
pathogenic insult, the commensal microbiota thriving on epithelial surfaces
serves as an invisible barrier to invading pathogens.

19. Development of gut-associated lymphoid tissues
(GALT)
M cells (or microfold cells) are cells found in the follicle-associated epithelium of the
Peyer's patch as well as in bronchus-associated lymphoid tissue (BALT). They transport
organisms and particles from the gut lumen to immune cells across the epithelial barrier,
and thus are important in stimulating mucosal immunity.

20. Functional barrier (the intestines)
M cells
Cellular elements
Anti-inflammatory
Cytokines
Mucus
PRR

21. The relationship between the host immune system and the commensal microbiota is
highly complex because these microbes possess many of the same traits as
pathogenic microorganisms.
Epithelium Intestines A principal function
of the microbiota
is to protect the
intestine against
colonization by
exogenous
pathogens and
potentially harmful
indigenous
microorganisms
via several
mechanisms,
which include
direct competition
for limited nutrients
and the modulation
of host immune
responses.

22. The immune system must coexist with commensal microbiota and maintain a state of
tolerance to self and innocuous environmental, yet be able to vigorously repel invasion
by a wide spectrum of pathogens.
Epithelium Intestines

23. Cells of the innate
immunity.
radaevamed@mail.ru

24. Cells of the innate immunity.
• Dendritic cell
• Natural helper
(NH)
Lymphocytes of innate immunity
• Natural killer
(NK)
Epithelial cells
Mast cells
Innate immunity protection is a task performed by cells of both
hematopoietic and non hematopoietic origin. Hematopoietic cells
involved in innate immunity responses include neutrophils,
eosinophils, basophil, monocytes-macrophages, dendritic cells,
mast cells, lymphocytes of innate immunity.
Cells of the innate immune
have PRRs (except for
lymphocytes of innate
immunity (NK, NH)).

25. Myelopoiesis.
Hematopoietic stem cells
have the ability to
differentiate into many types
of blood cells.
The two types of circulating
phagocytes (neutrophils and
monocytes), are blood cells
that are recruited to sites of
infection, where they
recognize and ingest
microbes for intracellular
killing.
Development of granulocytes and monocytes.
The total body neutrophil
content can be divided
conceptually into the following 3
compartments: the bone
marrow, the blood, and the
tissues. After differentiation in
the bone marrow, neutrophils
are released into the peripheral
blood and circulate for 7 to 10
hours before migrating into the
tissues, where they have a life

27. Populations of neutrophilic
granulocytes

28. Neutrophils
IL-23
IL-17
G-CSF
BLOOD
INFLAMMATION
НОРМА в крови
2 – 7,5 ·10 в 9 /л
Other mediators of
inflammation stimulate
bone marrow release
and promote
margination and
adhesion of neutrophils
to vascular endothelium
at the site of
inflammation. The time
for production of new
cells from the bone
marrow is 4 to 6 days
Neutrophils are white blood
cells that move from the
blood into the cells to kill
invading bacteria and fungi. If
neutrophil levels become too
high, neutrophilia results.

29. Neutrophils
• Neutrophils are the first inflammatory cells to
enter damaged tissue from the blood after tissue
damage has being caused. They are the
predominant cell 4 - 6 hours after the beginning of
an inflammatory reaction; at 12 hours there are
also substantial numbers of macrophages and at
24 hours there are equal numbers of neutrophils
and macrophages.
• The main function of neutrophils is
the protection of the body from the
local bacterial infections.

30. Microorganism
resident
macrophages
IL1β,
TNF-α
Neutrophil's chemotaxis
Lamellipodia
Neutrophils and monocytes migrate to extravascular sites of infection by
binding to endothelial adhesion molecules and in response to chemoattractants
that are produced on encounter with microbes in tissue. Leukocyte migration
from the blood into tissues is a multistep process that consists of initial loose
attachment of the leukocytes to endothelial cells (rolling), followed by firm
adhesion (adhesion) and transmigration through the endothelium (diapedesis).
If an infectious microbe
breaches an epithelium and
enters the subepithelial tissue,
resident macrophages
recognize the microbe and
respond by producing cytokines
(described in more detail later).

31. Neutrophils have three methods for
directly attacking microorganisms:
• phagocytosis (ingestion),
• release of soluble antimicrobials
(including granule proteins)
• generation of neutrophil
extracellular traps (NETs).
Neutrophils undergo apoptosis after the destruction of bacterial
cells. Receptors for the recognition and absorption by
macrophages appears on the membranes of neutrophils. The
macrophage then has the task of clearing both the dead
pathogens and the dead neutrophils.

32. Neutrophil extracellular traps

33. Monocytes
• Маke up about 5% to 10% of white blood cells and are a
heterogeneous group of cells that migrate into tissues and
differentiate into a diverse array of tissue-resident phagocytic
cells, including macrophages and dendritic cells.
• The mononuclear phagocyte system (monocytes/
macrophages) is a complex system that can be viewed in
different ways. Macrophages as recognized by Metchnikoff
can be found in all tissues, and as circulating cells called blood
monocytes.
• They, too, ingest microbes in the blood and in tissues. Unlike
neutrophils, monocytes that enter extravascular tissues survive
in these sites for long periods; in the tissues, these monocytes
differentiate into cells called macrophages

34. Blood monocytes and tissue macrophages
are two stages of the same cell lineage.
Resident macrophages are found in
connective tissues and in every organ in the
body

35. Macrophages functions:
• 1) phagocytosis of «non-self»;
• 2) phagocytosis of dead, dying, and aging cell ( are also
implicated in the removal of cell debris and apoptotic cell).
Macrophages clear apoptotic cells using scavenger receptors
and the vitronectin receptor).
• 3) pinocytosis macromolecules;
• 4) regulating repair and regeneration;
• 5) presentation of antigens (macrophages present antigen in
the pe-riphery to activated T cells.
• 6) secretion of biologically active substances (activated
macrophages secrete cytokines, enzymes, complement
system molecules, and procoagulant).

36. Macrophages
Tissue-
resident
macrophages
Inflammatory
macrophages
1) Regulating repair
and regeneration;
2) Detoxification;
3) Removal of dead
tissue cells - the main
function !!!!!
4) The cleansing blood
of degrading material,
fibrin clots, the bad
cholesterol, iron.
The macrophage then has the task of clearing
both the dead pathogens and the dead
neutrophils.
- If inflammatory macrophages recognise
damaged "non-self" (a greater percentage of
PAMPs), they will synthesize inflammatory
cytokines.
- If inflammatory macrophages recognise
damaged "self" (a greater percentage of
DAMPs), they will synthesize antiinflammatory
cytokines.

37. Functions of
tissue-resident
macrophages:
1) Regulating
repair and
regeneration;
2) Detoxification;
3) Removal of
dead tissue cells
- the main
function !!!!!
4) The cleansing
blood of
degrading
material, fibrin
clots, the bad
cholesterol, iron.

39. Receptors on macrophage
membrane:
• CD 14 – is receptor for a variety of bacterial products
(LPS);
• Scavenger receptors participate in the removal of many
foreign substances and waste materials in the living
body by extensive ligand specificity and a variety of
receptor molecules;
• Complement receptor – CR3;
• Fc gamma receptor I (FcγRI) – high affinity Rc for “tails”
(FC-fragment) of IgG.
• MHC I, MHC II.

40. Phagocytosis
• Phagocytosis - the process by which a cell,
such as a white blood cell, ingests
microorganisms, other cells, and foreign
particles.
• In an organism's immune system,
phagocytosis is a major mechanism used
to remove pathogens (it is especially
important for defense against extracellular
microbes) and cell debris.

41. Elie (Illya) Metchnikoff (also
spelled Mechnikov)
(1845–1916)
History of immunology
Elie Mechnikov was a Russian
zoologist best known for his
pioneering research into the
immune system. In particular, he is
credited with the discovery of
phagocytes (macrophages) in
1882, and his discovery turned out
to be the major defence mechanism
in innate immunity. He was
awarded the 1908 Nobel Prize in
Physiology or Medicine "in
recognition of their work on
immunity". In immunology he is
given an epithet the "father of
natural immunity or innate immunity"

42. 1) For example, when a macrophage
ingests a pathogenic microorganism,
the pathogen becomes trapped in a
phagosome which then fuses with a
lysosome to form a phagolysosome.
2) Within the phagolysosome,
enzymes and toxic peroxides digest
the pathogen. Bacteria, dead tissue
cells, and small mineral particles are
all examples of objects that may be
phagocytised.

43. Phases of phagocytoses
1. Chemotaxis.
2. Adhesion
(adherence)
3. Bacterium is
ingested
(formation of a
phagocytic cup),
forming
phagosome
4. Phagosome fuses
with lysosome.
5. Destruction of the
Microbes
6. Discharge of
waste materials
(exocytosis).
4 5
6
MHC II
+ antigens
On completion the membrane of the phagolysosome is
disrupted. Antigenic fragments may become diverted to
the acidic endosome compartment for interaction with
MHC class II molecules and antigen presentation.

44. Microorganism
resident
macrophages
IL1β,
TNF-α
Neutrophil's chemotaxis
Lamellipodia
Chemotaxis is the migration of polymorphonuclear
leukocytes and macrophages toward higher
concentrations of chemoattractants.
Сhemoattractant concentration increases around
microorganisms or damaged tissue.

45. Because of certain microbial defenses (production of M proteins
or slippery capsules), adherence of the phagocyte cell membrane
to the surface of the microbe may be difficult. Coating the surface
of the microorganism with complement proteins and antibody
proteins facilitates phagocytosis (process is called opsonization;
proteins are called opsonins).
Adhesion (adherence).
Phagocyte
cell
Antibody
Bacteria
Receptor

46. • The phagocyte engulfs the microbe with its plasma
membrane. The plasma membrane surrounds the
microbe and pinches off around the microbe, forming
a vesicle.
актин
Фагоцитарная
чаша
Formation of a phagocytic cup

47. Phagocytic cup

48. These signaling pathways trigger actin polymerization,
resulting in membrane extensions around the microbe
particles and their internalization, forming phagosomes

49. The formation of the phagosome

50. Phagosome fuses with
lysosome.
Phagosome
fuses with
lysosome.

51. Destruction of the Microbes
The phagosomes then fuse with lysosomes and, in
phagocytes, with preformed primary and secondary
granules. The resulting phagolysosomes contain an
arsenal of antimicrobial agents that then kill and
degrade the internalized microbes.
These agents include
antimicrobial proteins and
peptides (including defensins
and cathelicidins), low pH,
acid-activated hydrolytic
enzymes (including lysozyme
and proteases), and
specialized molecules that
mediate oxidative attack.

52. Degradation can be
oxygen-dependent or oxygen-independent:
• oxygen-dependent degradation depends on
NADPH and the production of reactive oxygen
species. Hydrogen peroxide and
myeloperoxidase activate a halogenating system,
which leads to the creation of hypochlorite and
the destruction of bacteria.
• Oxygen-independent degradation depends on
the release of granules, containing proteolytic
enzymes such as defensins, lysozyme, and
cationic proteins. Other antimicrobial peptides
are present in these granules, including lactoferrin

53. Discharge of waste materials
(exocytosis).
• On completion the membrane of the
phagolysosome is disrupted. Antigenic
fragments may become diverted to the
acidic endosome compartment for
interaction with MHC class II molecules and
antigen presentation. The process induces
secretion of toxic molecules and cytokines

54. Discharge of waste materials
(exocytosis).

55. Example of a bacterium that resists
digestion by a phagocyte.
1. Some intracellular pathogens,
including Mycobacterium tuberculosis, have
evolved strategies to inhibit phagosomal
maturation and can survive and replicate within
the immature phagosome.
2. Other pathogens, such as Escherichia
coli and Neisseria meningitides, have developed
mechanisms to fix, shed and/or degrade opsonins
to prevent activation of the immune response and
thus evade immune surveillance and
phagocytosis.

58. • Thank you for attention

59. Cells of the innate immunity:
Basophils, mast cells and eosinophils.
Dendritic cells. Nature killer.
Humoral elements.
The Compliment System

60. Basophils, mast cells and
eosinophils
• are critical to our response to parasites, particularly
helminths (worms). These cells also play an
important role in the development of allergies.
• Basophils, mast cells and eosinophils have
receptors for Ig (immunoglobulin) E.
• Ig E is essential for combating large parasitic worms.
• sIgE (antibodies) are responsible for the symptoms
experienced in allergic reactions

61. Eosinophils
Eosinophil granulocytes, usually called eosinophils
are white blood cells and one of the immune system
components responsible for combating multicellular
parasites
They usually bind to an antibody-coated parasite
through surface Fc receptors and release the contents
of their granules (degranulate) onto the parasite
surface. The granules contain peroxides and a toxin,
major basic protein, which kill the parasite.
The count can increase with allergic disorders, during
parasitic infections
Eosinophils are formed exclusively in the bone
marrow where they spend about 8 days in the
process of maturation before moving into the blood
vessels. They travel through the vessels for 8 to 12
hours before they finally arrive at destination tissues,
where they remain for 1 to 2 weeks.

62. Basophils and mast cells
Basophil granulocytes, mostly referred to as basophils, are the least common of the
granulocytes, representing about 0.01% to 0.3% of circulating white blood cells.
Basophils contain large cytoplasmic granules that obscure the cell nucleus under
the microscope when stained. However, when unstained, the nucleus is visible and
it usually has two lobes.
The mast cell, another granulocyte, is similar in appearance and function. Both cell
types store histamine, a chemical that is secreted by the cells when stimulated.
However, they arise from different cell lines, and mast cells usually do not circulate
in the blood stream, but instead are located in connective tissue. Like all circulating
granulocytes, basophils can be recruited out of the blood into a tissue when needed

63. Some distinctive and common
characteristics of basophils and mast cells
The stimulus for mast cell or basophil degranulation is often an
allergen. Mediators such as histamine, released by
degranulation, cause the adverse symptoms of allergy, but, on
the positive side, also play a role in immunity against parasites
by enhancing acute inflammation.

64. Basophils, mast cells and
eosinophils
• are critical to our response to parasites,
particularly helminths (worms).
• These cells also play an important role in
the development of allergies (a type I
hypersensitivity reactions).
• Basophils, mast cells and eosinophils
have receptors for Ig E.

65. Dendritic cells
❑ - Dendritic cells (DCs)
are so called because of
their many surface
membrane folds that are
similar in appearance to
dendrites of the nervous
system.
❑ - DCs are considered
cellular bridges between
the innate and adaptive
immune systems.

66. • Dendritic cells make contact with a pathogen
at the site of infection. They recognise
pathogen-associated molecular patterns
(microorganisms).
• They are highly phagocytic, take up microbes,
process the foreign microbial antigens, and
become mature APCs carrying the processed
antigen on their surface with specialized MHC
molecules.
• Dendritic cells communicate this encounter to
T lymphocytes in the lymph node (“antigen
presentation”)

67. Types of dendritic cells
Most classical DCs derive from one of two bone marrow precursors:
• a myeloid progenitor (DC1) that gives rise to myeloid DCs (localization –
diffuse –epidermis, mucosae, thymus, and T cell areas of secondary
lymphoid organs and tissues);
• a lymphoid progenitor (DC2) that develops into plasmacytoid DCs (T cell
areas of secondary lymphoid organs and tissues).

68. • Dendritic cells are generally viewed as the most effective of
the APCs. Because these cells constitutively express
a MHC class I, II molecules.
• The immune system typically uses different pathways to
eliminate intracellular and extracellular antigens.

69. As a rule, endogenous antigens (those generated within the cell) are processed in the
cytosolic or endogenous pathway and presented on the membrane with class I MHC
molecules.
If a virus had infected the APC (dendritic cell), viral peptides would also be presented,
allowing the immune system to recognize and kill the infected cell. The endogenous
pathway is used to present cellular peptide fragments on the cell surface on MHC
class I molecules.

70. • Exogenous antigens (those taken up from the extracellular environment
by endocytosis) are typically processed in the exogenous pathway and
presented on the membrane with class II MHC molecules.
• The exogenous pathway is utilised by specialised antigen presenting cells
to present peptides derived from proteins that the cell has endocytosed.
The peptides are presented on MHC class II molecules. Proteins are
endocytosed and degraded by acid-dependent proteases in endosomes.

71. • Remarkably, DCs are able to present internalized antigens to T cells via
MHC class I as well as class II molecules, in a phenomenon called cross-
presentation.
• In Cross-presentation, peptides derived from extracellular virus are
presented in the context of MHC class I and class II . The cell starts off
with the exogenous pathways but diverts the antigens (cytosolic
diversion) to the endogenous pathway.

72. APCs are a heterogeneous population of cells
that are impotent in innate immunity and play a
pivotal role in the induction of functional activity
of T helper cells.

73. Innate lymphoid cells

74. Natural killer (NK) cells
• They are derived from the bone marrow
and morphologically have the appearance
of large granular lymphocytes.
• CD16 and CD56 are important markers of
NK cells

75. Natural killer (NK) cells

76. Natural killer (NK) cells
The function of NK
cells is to recognize
and kill through
apoptosis:
• •virus-infected cells;
• certain tumor cells.

77. • Activation of NK cells leads to lysis of target cells, which is mediated
by perforin and granzymes, and cytolytic granule mediated cell
apoptosis .
• Upon release in close proximity to a cell slated for killing, perforin forms
pores in the cell membrane of the target cell, creating an aqueous channel
through which the granzymes and associated molecules can enter,
inducing either apoptosis or osmotic cell lysis.

78. Лектор: Радаева О.А.
Humoral elements.
Molecules of the innate
immune system

79. Molecules of the innate immune
system
1. The complement system
2. The interferons system
3. Antimicrobial peptides (Lysozyme,
β-lysin, Lactoferri, Collectins,
Defensins)
4. Acute phase proteins (pentraxins,
fibronectin, haptoglobin)

80. The complement system
Jules Bordet(1870-1961)
Paul Ehrlich (1854-1915)

81. The complement system is a
proteins, that widely distributed
throughout body fluids and
tissues without adverse effect. At
sites of infection, however, they are
activated locally and trigger a series
of potent inflammatory events.
The complement system
activates through a triggered-
enzyme cascade. In such a
cascade, an active complement
enzyme generated by cleavage of its
zymogen precursor then cleaves its
substrate, another complement
zymogen, to its active enzymatic
form. This in turn cleaves and
activates the next zymogen in the
complement pathway.
Over 30 proteins (nine major components
- abbreviated as C') and protein
fragments make up the complement
system. Complement components
constitute approximately 15% of the
globulin protein fraction in plasma, and
their combined concentration can be as
high as 3 mg/ml.

82. The functions of the complement
system include:
1. Cell Lysis – rupturing membranes of
foreign cells;
2. Opsonisation – enhancing
phagocytosis of antigens;
3. Chemotaxis – attracting
macrophages and neutrophils;
4. The triggering and amplification of
inflammatory reactions

83. • Nine major components:
the first component of the pathway, C1, is a complex molecule
comprising a large recognition unit termed C1q and two
molecules each of C1r and C1s, the enzymatic units of the
complex С2, C3, C4, C5 split into two parts (C2a/C2b, C3a/
C3b, C4a/C4b, C5a/C5b). As a rule, the larger fragment of a
cleaved complement component is designated with the suffix
“b,” and the smaller with the suffix “a.” However, there is one
exception to this rule: the larger, enzymatically active form of
the C2 component is named C2a.
• the components C6, C7, C8, and C9 not disintegrate when
activated (membrane attack proteins). The proteins of the
membrane attack complex (MAC) insert into the cell
membranes of invading microorganisms and punch holes that
result in lysis of the pathogen. The complement components
of the MAC are C5b, C6, C7, C8, and multiple copies of C9.

84. Cytolytic function of the
complement system

85. The complement cascade may be activated by
any of three pathways

86. The Classical pathway
• The classical pathway links to the adaptive
immune system. The classical pathway is
activated by antibody bound to antigen

87. С1qrs

88. C1qrs
BACTERIA

89. С3 конвертаза
С4b
C2b
С4a C2а
С4bC2b

90. С3 конвертаза
мембранная С4bC2b
С4bC2bС3b
С5 конвертаза

91. The membrane attack complex
• Membrane-bound C5bC6C7 recruits C8 from the plasma,
and, finally, multiple copies of C9 are incorporated in the
complex to form the MAC.

92. • The membrane attack
pathway results in the
formation of a transmembrane
pore.
• The pore has an inner
diameter approaching 10 nm:
• allowing the free flow of solutes
and electrolytes across the
cell membrane;
• because of the high internal
osmotic pressure, causing the
cell to swell and sometimes
burst.

93. Видео

94. The lectin pathway
The lectin pathway differs from the classical pathway only in the
initial recognition and activation steps. The C1 complex is
replaced by a structurally similar multimolecular complex,
comprising the C1q-like recognition unit mannan-binding lectin
(MBL)

95. The alternative pathway
Initiation of the alternative pathway of complement activation is independent
of antibody-antigen interactions.
С3
C3b C3a
Spontaneous
hydrolysis of
soluble C3 to C3b
Фактор В
С3-convertase – С3bВ

96. The membrane attack complex
• Membrane-bound C5bC6C7 recruits C8 from the plasma,
and, finally, multiple copies of C9 are incorporated in the
complex to form the MAC.

98. Membrane-binding
components or opsonins
The term opsonisation refers
to the capacity of antibodies
and com-plement
components (as well as
other proteins) to coat
dangerous antigens that can
then be recognised by Fc
receptors (for antibodies) or
complement receptors (for
complement components)
on phagocytic cells. Binding
of complement-coated
antigen by phagocytic cells
results in complement re-
ceptor-mediated
phagocytosis and antigen
destruction.
С3b
СR
1
Фактор I
For C3 and C4, the larger fragments, C3b and
C4b, serve as opso-nins, enhancing
phagocytosis by binding to microbial cells and
serving as binding tags for phagocytic cells
bearing receptors for C3b or C4b.

99. • Initiation of (acute)
inflammation by
direct activation of
mast cells (C3a,
C5a).
• Chemotaxis.
C3a and C5a are
structurally similar,
small proteins that
promote inflammation
and serve as
chemoattractants for
certain classes of
leukocytes

100. The interferons system
• IFNs belong to the large class of proteins
known as cytokines, molecules used for
communication between cells to trigger
the defenses of the immune system.

101. Human interferons have been classified
into three major types
Types:
• Interferon type I: IFN α, IFN β, IFN ω, IFN ε,
IFN κ;
• Interferon type II (IFN-γ in humans);
• The recently classified type III interferon
group consists of three IFN-λ (lambda)
molecules called IFN-λ1, IFN-λ2 and IFN-λ3.

103. Common characteristic:
Like all cytokines, the ability of a cell to respond
to IFN is completely dependent on the presence
of its cognate receptor on the surface of the
target cell.
Human IFN valid only on human cells (species
specificity).
IFN inhibits the proliferation of various viruses in
the cells (universal mechanism of action).

104. Interferon type I: IFN α, IFN β
Основные клетки-продуценты ИФН I:
• The main producer cells IFN I:
• 1) plasmacytoid dendritic cells;
• 2) monocytes / macrophages;
• 3) epithelial cells;
• 4) fibroblasts (IFNβ, IFNα);
• 5) virus-infected nucleated cells
Peak production of type I interferons
observed 6-12 h after virus infection.

105. Functions:
I типа:
Antiviral function.
1 A virus is a small infectious agent that
replicates only inside the living cells of
other organisms.
2 A virus-infected cell releases viral particles that
can infect nearby cells. However, the infected
cell can prepare neighboring cells against a
potential infection by the virus by releasing
interferons.

106. 1. Interferon binds to the cell receptor.
2. The signal is transmitted to the nucleus. Protein
synthesis in the cell is blocked.
3. The virus penetrates the cell but can not replicate.
Interferon does not kill the virus.
4. Inteferon blocks viral replication in human cells.

109. If antiviral immunity is working correctly, a
viral infection last for ten days.

110. • Immunomodulatory function. Another
function of interferons is to upregulate MHC I
and MHC II, and increase
immunoproteasome activity.
• Antitumor functions of type I interferons.
IFN-α can act indirectly on the tumor by inhibiting
angiogenesis which is induced by the tumors and is
required to promote their growth and metastasis.

111. Interferon type II (IFN-γ in humans).
The main producer cells:
NK,
macrophages and dendritic cells;
cytotoxic CD8 + T lymphocytes,
ThI lymphocytes.
Synthesis of IFNγ reaches its maximum 48-72 hours after
stimulation of cells.
Note: the antiproliferation and antiviral
activities are weaker than those of IFN
alpha and IFN beta. IFN gamma is the most
potent of the three at macrophage
activation and in inducing class II MHC
expression

112. - IFN-gamma enhances the microbicidal function of
macrophages through formation of nitric oxide and
reactive oxygen intermediates (ROI)
- IFN-gamma stimulates the expression of class I and class
II MHC molecules and co-stimulatory molecules on
antigen presenting cells
- IFN-gamma promotes the differentiation of naive helper
T cells into Th1 cells
- IFN-gamma activates polymorphonuclear leukocytes
(PMN) and cytotoxic T cells and increases the cytotoxicity
of NK cells.

113. 1. Russian healthcare promotes the use of interferons and
interferon inductors as a prophylaxis and treatment of
influenza and other viral infections.
2. Interferons can selectively inhibit viral replication process
without compromising cell metabolism. Genetically
engineered recombinant compounds of interferon
(Grippferon, Viferon, Reaferon) are widely used in
medical practice.
3. Interferon therapy is used (in combination with
chemotherapy and radiation) as a treatment for some
cancers.
Interferons used therapeutically are
manufactured using recombinant DNA
technology.

114. Бактерицидные пептиды
• Lysozyme (Lysozyme, also known as
muramidase, are glycoside hydrolases (enzyme))
Lysozyme is abundant in a number of
secretions, such as blood, lymph, tears,
saliva, human milk, and mucus. It is also
present in cytoplasmic granules of the
macrophages and the
polymorphonuclear neutrophils. Ly-
sozyme is not detected in the
cerebrospinal fluid and the anterior
chamber. Macrophages and neutrophils
synthesize lysozyme.
The enzyme functions by attacking
peptidoglycans (found in the cell walls of
bacteria). Lysozyme kills bacteria,
especially Gram-positive.

115. Acute phase proteins and
their functions.
These molecules include:
• pentraxins (C-reactive protein (CRP), serum
amyloid protein A (SAA));
• complement components;
• opsonic proteins such as mannose-binding protein
(MBP), metal-binding proteins and protease
inhibitors;
• haptoglobin, hemopexin, ceruloplasmin;
• Blood coagulation factors (fibrinogen, prothrombin,
factor VIII, and plasminogen).

116. CRP
• CRP was so named because it was first
identified as a substance in the serum of
patients with acute inflammation that reacted
with the C-polysaccharide of Pneumococcus.
CRP binds to the phosphocholine expressed on
the surface of dead or dying cells and some
bacteria. This activates the complement system,
promoting phagocytosis by macrophages, which
clears necrotic and apoptotic cells and bacteria.
• Diagnostic use. CRP is used mainly as a
marker of inflammation.

117. Pattern recognition receptors
(PRRs)
• are proteins expressed by cells of the
innate immune system to identify
pathogen-associated molecular patterns
(PAMPs), which are associated with
microbial pathogens or cellular stress, as
well as damage-associated molecular
patterns (DAMPs), which are associated
with cell components released during cell
damage.

118. PRR types and localization
• Secreted (soluble) PRRs.
• Membrane-bound PRRs
- Endocytic PRRs
- Signaling PRRs
• Cytoplasmic PRRs

119. Secreted (soluble) PRRs.
• A number of PRRs do
not remain associated
with the cell that
produces them.
• One very important
collectin is mannan-
binding lectin (MBL), a
major PRR of the innate
immune system. MBL
predominantly
recognizes certain sugar
groups on the surface of
microorganisms but also
binds phospholipids.
Once bound to the
ligands MBL and initiate
the lectin pathway of
complement activation.

120. Membrane-bound PRRs.
Endocytic PRRs
• Endocytic PRRs - promote the attachment,
engulfment and destruction of microorganisms
by phagocytes, without relaying an
intracellular signal. These PRRs recognize
carbohydrates and include mannose receptors
of macrophages, glucan receptors present on
all phagocytes and scavenger receptors that
recognize charged ligands, are found on all
phagocytes and mediate removal of apoptotic
cells.

121. Example
The mannose receptor present on the surface of
macrophages. The receptor recognises terminal
mannose, N-acetylglucosamine residues on glycans
attached to proteins found on the surface of some
microorganisms. Binding to the receptor causes
phagocytosis and destruction of the foreign cell.

122. Membrane-bound PRRs. Signaling PRRs
Signaling PRRs include the large
families of membrane-bound Toll-
like receptors.
Signaling PRRs recognize
evolutionarily conserved structures
on pathogens, PAMPs, and trigger
innate immune responses,
including production of pro-
inflammatory cytokines and type I
IFN.
To date, 10 TLRs have been
identified in humans, and they
each recognize distinct PAMPs
derived from various microbial
pathogens, including viruses,
bacteria, fungi, and protozoa.

123. Overview of innate immune signalling pathways and
components.
BACTERIA VIRUS
Antibacterial
protection
IL-1, pro- inflammatory cytokines
Antiviral
protection
Type I IFN (IFN-α, IFN-β)

125. Cytokines
Cells communicate
with words-cytokines

126. Cytokines
❑ Cytokines are a large, diverse family of small
proteins
❑ Cytokines are mediators of intercellular
interaction
❑ Cytokines are produced by a broad range of
cells, including immune cells like macrophages,
B lymphocytes, T lymphocytes and mast cells,
as well as endothelial cells, fibroblasts, and
various stromal cells; a given cytokine may be
produced by more than one type of cells

127. Nomenclature

128. This action may occur in
• an autocrine (acts on same cell),
• paracrine (acts on nearby cell)
• or endocrine (acts on distant cell; not the
normal manner for cytokine responses) manner.
Receptor engagement triggers intracellular
signalling cascades leading to altered gene
expression in the target cell, which lead to a
biological effect. Differentiation, proliferation and
activation of the target cell are all effects which
can be detected after cytokine stimulation.

129. Biological functions of
cytokines:
• 1. Control of the embryonic development
• 2. Regulation a number of physiological
functions
• 3. Regulation of the body's defenses at the
local and systemic levels.
• 4. Regulation of development of allergic,
autoimmune and other immune-pathological
processes.
• 5. Participation in the regulation of tumor cell
transformation and tumor progression.
• 6. Regulation of tissue regeneration.

130. Cytokines exhibit the attributes of
• pleiotropy,
• redundancy,
• synergism,
• antagonism, and
• cascade induction,
• short lived,
which permit them to regulate cellular
activity in a coordinated, interactive way

131. Cytokines
• A cytokine that induces different biological effects
depending on the nature of the target cells is said to
have a pleiotropic action, whereas two or more
cytokines that mediate similar functions are said to
be redundant.
• Cytokine synergy occurs when the combined effect
of two cytokines on cellular activity is greater than the
additive effects of the individual cytokines.
• In some cases, the effects of one cytokine inhibit or
antagonize the effects of another.
• Cascade induction occurs when the action of one
cytokine on a target cell induces that cell to produce
one or more additional cytokines.

132. Proinflammatory or
anti-inflammatory cytokines
• A proinflammatory cytokine is a cytokine that promotes
systemic inflammation. Interleukin (IL)-1 and tumor necrosis
factor (TNF) are proinflammatory cytokines, and when they are
administered to humans, they produce fever, inflammation,
tissue destruction, and, in some cases, shock and death.
• The anti-inflammatory cytokines are a series of
immunoregulatory molecules that control the proinflammatory
cytokine response
• The net effect of an inflammatory response is determined by
the balance between pro-inflammatory and anti-inflammatory
cytokines.