Download Innate immunity/ cont…II.Second line: 2.Phagocytosis:

Phagocytosis:
Phagocytes (eating cells) are body cells
specialized for capture, ingestion and
destruction of antigens (as bacteria and fungi),
debris, and produce inflammatory molecules
which regulate other components of the
immune system. They express a wide range of
surface receptors that allow them to identify
microorganisms. Also, phagocytosis can be
enhanced by antibodies, complement and
acute phase proteins (all called opsonins and
act as a bridge between the antigens and
phagocytic cells). They are of TWO types:
1. 1.Polymorphnuclear leucocytes
(microphages); mainly neutrophils.
They are short-lived cells with a half
life of 6 hours.
2. Mononuclear cells (macrophages);
Monocytes after 7-10 hours in the blood
they migrate to tissues. In C.T.
(histiocytes), or fixed in RES (e.g., liver,
spleen, L.N., B.M… etc.).
The process of phagocytosis include the
following stages:
 Granulocytes
– Polymorphonuclear leukocytes
(PMN, neutrophils)
– Eosinophils
– Basophils (blood)
– Mast Cells (tissues)
fight pathogens
inflammation
allergic and
hypersensitivity reactions
 Mononuclear Phagocytes (RES)
– Monocytes (blood)
– Macrophages (tissue)
fight pathogens
inflammation
cytotoxicity
immune regulation
Neutrophils
(PMN)




Present in blood (60-70% of WBC)
Not normally present in tissues
Short lifespan - 12 hours
Functions:
– First cell at the site of infection/injury
 Ingest and kill microbes after bactericidal
mechanisms activated (binding to pathogen)
Mononuclear
Phagocytes
 Blood - monocytes (1-6% WBC)
 Tissues - macrophages
– mature form of monocytes
– found in tissues (ex., gastrointestinal tract, lung, liver,
brain, skin, spleen); reticuloendothelial system (RES)
 Functions:
– Phagocytize and kill after bactericidal mechanisms
activated
– Produce cytokines/chemokines (initiate inflammation)
– Antigen presentation (activate adaptive immunity)
– Tumor surveillance and cytotoxicity
Reticuloendothelial System
 Consists of fixed and wandering
macrophages located throughout the body
(tissues, sinusoids, lymph system)
 Major locations: Liver and Lung
 Functions: antibacterial resistance, tumor
resistance, defense against shock, antigen
processing, lipid metabolism, protein
turnover, iron metabolism
 A. Chemotaxis,Migration, &
Attachment:
 If epith. lining is breached by
microbes, resident phagocytes
are attracted (influx) to the site
by chemotactic substances as
bacterial endotoxins (LPS),
serun C5a, IL-8, and leukotriene
B4.
 The macrophages produce cytokines as IL-1 &
TNF.These activate endothelial cells of nearby
venules to produce adhesion molecules
(selectin, integrins, & ICAM) and chemkines
(e.g.,IL-8) which mediate MIGRATION of
leucocytes & monocytes from the blood to
tissues (diapedesis).
 The phagocytes have receptors on their
surface through which they ATTACH nonspecifically to m.o. Examples: Receptors for
bacterial endotoxines, for mannose residues
on glycoprotein of many bacteria,
unmethylated bacterial DNA & double stranded
RNA of many viruses. The attachment and
ingestion is enhanced if microbes are coated
with IgG or C3b (opsonization).
Pattern Recognition Receptors (PRR)
Three broad classes based on expression profile,
localization, function
PRR that signal an infection:
1. Toll Receptor Family (Toll-like Receptor “TLR “ 111)
– Expressed externally or internally
– Binding activates “pro-inflammatory” signaling pathways
2. Phagocytic (endocytic) PRR
– Expressed on the surface of phagocytic cells
– Mediate uptake of microbe into phagocytes
3. Secreted PRR
– Secreted by MP, epithelial cells, hepatocytes
– Activate complement, opsonins, function as accessory
proteins for Pathogen-Associated Molecular Pattern (PAMP)
recognition on target cells such as microbes.
Toll-Receptor Family:
How do Macrophages Identify Microbes?
Pattern Recognition Receptors (PPR )
– Recognize pathogen associated molecular
patterns (PAMP); conserved molecular
patterns on microbes
– Identify a class of microbes; ex., LPS, LTA,
peptidoglycan, lipoarabinomannan, dsRNA, mannose,
b-glycans
– PAMP are often essential for microbe survival
 Action Time
– Immediate activation of effectors
– Delays need for adaptive immunity
Leukocyte Adhesion
selectins
 B. Ingestion:
 The phogocytes engulf the antiges
(e.g. organism) by extending
pseudopods around them. Then the
organism is included into vacuole
called PHAGOSOME. Lysosomal
granules fuse with the phagosome
forming PHOGOLYSOSOME. Then is
followed by DIGESTION of organism.
C. Intracellular killing or Digestion:
 Anti-microbial and cytotoxic substances are
produced that destroy phagocytosed m.o. by TWO
mechanisms:
 1. Oxygen-dependent (Respiratory Burst):
 This killing system is mediated by NADPH oxidase
enzymes complex, which converts oxygen into
reactive oxygen species such as hydrogen
peroxide and superoxide that are lethal to
micoorganisms. When combined with
myeloperoxidase, hypochlorous ions (HOCl -,
analogous to bleach) are highly effective oxidants
and anti-microbial agents.
 2. Oxygen-independent:
 Killing in this system is the result of
lysozomal contents which include
lysozyme, lactoferrin, a group of cationic
proteins (defensins), and hydrolytic and
proteolytic enzymes.
 Some bacteria resist destruction for long
periods, others multiply within the
phagocytes (M. tuberculosis, M. leprae).
Wandering phagocytes transport these
m.o. to new places (spread infection).
Functions of macrophages:
1. Initiation and amplification of the
inflammatory response.
2. Killing of microorganisms.
3. Resolution and repair of
inflammation.
4. Link between innate and adaptive
immune system.
 Cont…/Second line of innate immunity…
 3. Natural Killer (NK) cells:
 They comprise 10-15% of the peripheral
lymphocytes. They are CD3 (-), CD11b
(+), CD16 (+), and CD 56 (+). They have
non-specific CYTOTOXIC activity
against tumour cells, graft cells, & virus
infected cells. Their function is NOT
restricted by MHC. Their activity is
increased by INF, IL-2 & 12. They have
surface receptor to IgG - Fc (CD16).
 4. Inflammatory barriers:
 Inflammatory response has 3 events:
 1. Vasodilatation of nearby capillaries
leading to redness of tissues, increase
tissue temperature, increase capillary
permeability and influx of fluid and cells
(exudate) causing oedema. 2. Influx of
phagocytes which engulf m.o. & release
lytic enzymes that can result in tissue
damage. 3. Chemical mediators are
released from damaged tissues, m.o.,
leucocytes & plasma enzyme systems (
histamine,kinin,fibrine,cytokines &APP).
Functions of Phagocytes:
Inflammatory Responses
Injury or
 Constitutional Factors affecting
Innate Immunity:
 1. Species : Some organisms are
pathogenic to certain species, e.g.,
M.leprae affects man, but not monkey.
 2. Race : Example; Negroes & red Indians
are more susceptible than whites to M.
tuberculosis.
 3. Individuals: GENETIC influences
susceptibility (e.g., G6PD deficiency
resistant to malaria). Extremes of AGE ;
due to immaturity or aging of immune
system in children & old respectively.
 4. Nutritional status: Under nutrition
increases susceptibility to disease.
 5. Hormones: Example: corticosteroid &
other immunosuppressive drugs,
diabetics (lack insulin) or pregnancy
increase susceptibility to infections.
 Cytokines of innate Immunity:
 From activated macrophages: IL-1, IL2,TNF which increase extravasation of
neutrophils, induce coagulation &
increase vascular permeability. Also IL12 which activate NK cells. INF-gamma
(from NK) activate macrophages. INFalpha (from viral infected cell) inhibits V.
 4. Nutritional status: Under nutrition
increases susceptibility to disease.
 5. Hormones: Example: corticosteroid &
other immunosuppressive drugs,
diabetics (lack insulin) or pregnancy
increase susceptibility to infections.
 Cytokines of innate Immunity:
 From activated macrophages: IL-1, IL2,TNF which increase extravasation of
neutrophils, induce coagulation &
increase vascular permeability. Also IL12 which activate NK cells. INF-gamma
(from NK) activate macrophages. INFalpha (from viral infected cell) inhibits V.
Summary:
 Aims of the immune system:
– I. Protection: by specific &non-specific
immunity
– 2.Hypersensitivity (I,II,III& IV).
– 3.Tolerance and autoimmunity.
– 4. Immunodeficiency diseases.
–Introduction to immunological words
as antigens, antibodies, complement ,T
cells, B-cells, HLA (MHC) system, CD
markers, Monoclonal antibodies &
cytokines.
–Branches of recent and current
IMMUNOLOGY.
–Innate immunity. Details.