Download Type of Innate immune

Key Molecules in immune response :
Antigens , antibodies , MHC, TCR, adhesion molecules (CD), Cytokines.
Several types of molecules play vital roles in immune responses. Antibodies are substances which
provoke an immune response. Antibodies are not only the surface receptors of B cells that recognize
specific antigens, but once the appropriate B cells are activated and differentiate into plasma cells;
antibodies also are secreted into blood and body fluids in large quantities to prevent that antigen from
causing damage. T cell have similar receptors for recognizing antigens, Known as T-cell receptors.
Major histocompatibility complex (MHC) molecules provide a means of self recognition and also play a
fundamental role in T lymphocyte effector functions. Effector mechanisms are often dependent on
messages from initiating or regulating cells, soluble mediators which carry message between cells are
known as interleukins or cytokines.
Antigens:
Antigens are able to provoke an immune response and react with the immune products. They react both
with the T-cell recognition receptor and with antibody. An antigenic molecule may have several antigenic
determinants (epitopes), each epitope can bind with an individual antibody, and a single antigenic
molecule can therefore provoke many antibody molecules with different binding sites. Some low
molecular –weight molecules, called haptens, are unable to provoke an immune response themselves,
although they can react with existing antibodies. Such substances need to be coupled to carrier molecule
in order to have sufficient epitopes to be antigenic. For some chemicals, such as drugs, the carrier may be
a host (auto) protein. The tertiary structure as well as the amino acid sequence, is important in
determining antigenicity. Pure lipids are not immunogenic and nucleic acids are also poor antigens.
Antigens are conventionally divided into:
Thymus dependent antigens which are required T-cell participation to provoke the production of
antibodies; most proteins and foreign red cells are examples.
Thymus-independent antigens require no T-cell cooperation for antibody production; they directly
stimulate specific B lymphocytes by virtue of their ability to cross-link antigen receptors on the B-cell
surface, produce predominantly IgM and IgG2 antibodies and provoke poor immunological memory.
Such antigens include bacterial polysaccharides (found in bacterial cell walls). Endotoxin another
thymus-independent antigen, not only causes specific B-cell activation and antibody production but acts
as a polyclonal B-cell stimulant as well. Factors other than the intrinsic properties of the antigen can also
influence the quality of the immune response.
Factors influencing the immune response to an antigen, i.e its immunogenicity.
1-Nature of molecules
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Protein content
Size
Solubility
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2- Dose
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Low dose----antibody high affinity and restricted specificity
Moderate dose----- antibody mixed affinity and broad specificity
High dose ------------ tolerance
3- Route of entry
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ID,IM,SC ------regional lymph nodes
IV---------------- spleen
Oral------------- Peyers patches
Inhalation----- bronchial lymphoid tissue
4- Addition of substances with synergistic effects
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e.g. a adjuvant , other antigens
5- Genetic factors of recipient animal
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Species differences
Individual differences
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Non-specific immunity ( Innate Immunity)
Introduction
During evolution, an extremely complex system of anti-infections defenses has emerged. But at the same time
as vertebrates and mammals developed their defenses, microbes continued evolving as well, and many became
adept at avoiding the consequences of the anti-infections defense mechanisms. The interplay between host
defenses, microbial virulence, and microbial evasion mechanisms determines the outcome of the constant
encounters between host and pathogenic organisms.
Immunity:
State of being immune.
Immune:
Having a high degree of natural or acquired resistance to a disease. By extension, the term indicate the altered
state of an individual that result from immunization with any antigen. An animal can be immune by means of
exposure to natural infection, antigen and vaccine.
Immunology:
Science deals with study the immune response.
Immune response:
Specific response of an animal to antigenic stimulation. The immune response may take the form of antibody
production, cell-mediated immunity or tolerance.
II. Nonspecific Anti-Infectious Defense Mechanisms
Nonspecific defense mechanisms play a most important role as a first line of defense, preventing penetration
of microorganisms beyond the outer exposed surfaces of the body. The following is a brief description of the
most important nonspecific defense mechanisms.
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Innate immunity (
Non specific immune response)
First line:
1) Mechanical barriers
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- Intact skin
- Mucous coat
- Mucous secretion
- Blinking reflex and tears
- The hair at the nares
- Coughing and sneezing reflex
2) Chemical & biochemical inhibitors
- Sweet and sebaceous secretion
- Hydrolytic enzymes in saliva
- HCl of the stomach
- Proteolytic enzyme in small intestine
- Lysozyme in tears
- Acidic pH in the adult vagina
3) Normal bacterial flora
- Competition for essential nutrients
- Production of inhibitory substances
Second line:
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2- Phagocytes
Specialized cells for capture, Ingestion and destruction of invading microorganisms
* Polymorphonuclear leucocytes, mainly neutrophils:
granulocytes circulate in blood
* Mononuclear cells (macrophages)
- Monocytes in blood
- Histocytes in connective tissues
- Fixed reticuloendothelial cells in liver spleen, lymph nods, bon marrow
B- Soluble factors
1- Acute phase protein (Plasma protein, CRP=C reactive protein, Fibrin.)
2- Complement
(proteins in serum, body fluids)
2- Interferons
(Proteins against viral infections)
3- Properdin
(Complement activation)
4- Beta lysine (Antibacterial protein from Platelets)
5- Lactoferrrin,Transferrin (Iron binding protein)
6- Lactoperoxidase
(Saliva & Milk)
7- Lysozyme (Hydrolyze cell wall)
Interferons:
Proteins usually produced by virally infected cells
* Types of interferon's:
1- Alpha interferon Secreted by Macrophages
Induced by Viruses or Polynucleotide
2- Beta interferon Secreted by Fibroblasts, Viruses
3- Gamma interferon T- lymphocytes, Specific antigens
Protective action of interferons:
1) Activate T-cells
2) Activate macrophages
3) Activate NK
Phagocytosis
The engulfment, digestion, and subsequent processing
of microorganisms by macrophages and neutrophils
1) Chemotaxis & attachment:
a- Attraction by chemotactic substances
(microbes, damaged tissues)
b- Attachment by receptors on surfaces
of phagocytes
2) Ingestion:
* Phagocyte pseudopodia surround
organism forming phagosom
* Opsinins and co-factors enhance
phagocytosis
* Fusion with phagocyte granules and release digestive, toxic contents
3- Killing (two microbicidal routes)
a- Oxygen depended system (powerful microbicidal
agents)
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Oxygen converted to superoxide, anion,
hydrogen peroxide, activated oxygen and
hydroxyl radicals.
b- Oxygen-independent system (anaerobic
conditions)
Digestion and killing by lysozyme. Lactoferrin,
low pH, cationic proteins and hydrolytic and
Proteolytic enzymes .
Type of Innate immune
1.Inducible Nonspecific Responses:
A. Physiologic barriers
1. Including fever and Temperature normal body temperature inhibits growth of some pathogens.
2. Fever response inhibits growth of some pathogens.
3. Low pH Acidity of stomach contents kills most ingested microorganisms.
4. Lysozyme cleaves bacterial cell wall.
5. Interferon induces antiviral state in uninfected cells release of interferons, activated when
infectious agents manage to invade, particularly effective in preventing viral replication.
6. Complement lyses microorganisms or facilitates Phagocytosis.
7. Toll-like receptors recognize microbial molecules, signal cell to secrete immunostimulatory
cytokines.
8. Collectins disrupt cell wall of pathogen.
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9. Oxygen potential
B. Phagocytic/endocytic barriers:
Various cells internalize (endocytose) and break down foreign macromolecules. Specialized cells
(blood Monocytes, neutrophils, and tissue macrophages) internalize. (Phagocytose), kill, and
digest whole microorganisms.
As a microbe penetrates beyond the skin or mucosal surface, it will
encounter cells able to ingest it.
Two types of cells are particularly adept at no immune Phagocytosis: tissue macrophages and
granulocytes (particularly neutrophils).This non-immune Phagocytosis involves a variety of
recognition systems. About 90% of invaded microbe was eliminated by phagocytosis.
C. Inflammatory barriers:
Tissue damage and infection induce leakage of vascular fluid, containing serum proteins with
antibacterial activity, and influx of phagocytic cells into the affected.
D- Including fever and release of interferon’s, activated when infectious agents manage to invade,
particularly effective in preventing viral replication.
E- Activation of the Complement System :
1. A variety of microorganisms (bacteria, fungi, viruses, and parasites) can activate complement by the
Classical pathway.
2. CR1 and CR3 receptors are able to interact with C3b and iC3b on the microbial membrane, generated
as a consequence of complement activation by the alternative pathway, a property common to many
bacteria in most cases where adequate studies have been carried out, polysaccharidic structures have
been proven to be responsible for complement activation of the alternative pathway. This activation
will lead to Phagocytosis.
3. Mannose receptors on phagocytic cells may mediate ingestion of organisms with mannose-rich
polysaccharides, such as Candida albicans. Mannose .Diagrammatic representation of the different
receptors that may mediate non immune Phagocytosis (MBP = mannose-binding protein; CRP = Creactive protein.
4.
C-reactive protein binds to certain bacterial polysaccharides and has very similar effects to the
mannose binding protein, activating complement and promoting Phagocytosis, both through CR1 and
CR3, as well as by other receptors, including the FcgRI and the C1q receptor, both of which bind this
protein.
F. Acute Phase Reaction and Leukocyte Chemotaxis.
The initial recognition by phagocytes and the activation of the complement system by the alternative
pathway, by themselves, may not be sufficient to eradicate the invading microorganism, but the response
is quickly amplified by a multitude of cytokines released by macrophages activated as a consequence of
Phagocytosis.
1.
IL-1 and TNF-a cause an increase in body temperature, mobilize neutrophils from the bone marrow,
and unregulated the synthesis of a variety of proteins known as acute phase reactants, including Creactive protein and the mannose-binding protein mentioned above.
2. TNFa and IL-1 up-regulate the expression of cell adhesion molecules in the endothelial cells of
neighboring endothelial cells, thus promoting adherence.
3. IL-8 has Chemotactic properties. Together with other chemotactants, such as C5a and bacterial
peptides, it attracts neutrophils toward the focus of infection. of leukocytes, and increase vascular
permeability. Both factors facilitate the migration of leukocytes off the Vessels, toward the focus of
infection.
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Examples of Infectious Agents Able to Activate the Alternative. Pathway of complement without
apparent participation of Specific antibody
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a. Bacteria ---Streptococcus pneumonia, Staphylococcus aureus and S. epidermidis
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b. Fungi ----
Candida albicans
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c. Parasites rodhaini
H. influenzae Type b Trypanosoma Cyclops, Schistosoma mansoni and Babesia
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d. Viruses --------Vesicular stomatitis virus
G. Natural Killer (NK) Cells are able to destroy viral infected cells as a consequence of the delivery of an
activating signal in the absence of an inhibitory signal.
H. g/D T Lymphocytes are predominantly localized to the mucosal epithelia, where they appear to recognize
infected epithelial cells by a non-immunological mechanisms (i.e., not involving the T-cell receptors),
which are subsequently destroyed.
I. Natural Antibodies
Preexisting antibodies may play a very important anti-infectious protecting role. Natural antibodies may arise as
a Consequence of cross-reactions, as exemplified in the classic studies concerning the isoagglutinins of
the ABO blood group system (i.e., circulating antibodies that exist in a given individual and are able to
agglutinate erythrocytes carrying alloantigen of the ABO system different from those of the individual
himself).
A. The Origin of the AB Isoagglutinins
1. Chickens are able to produce agglutinins recognizing the AB alloantigen, but only when fed conventional
diets; chicks fed sterile diets do not develop agglutinins. Furthermore, anti-A and anti-B agglutinins
develop as soon as chicks fed sterile diets after birth are placed on conventional diets later in life.
2. These observations pointed to some dietary component as a source of immunization. It was eventually
demonstrated that the cell wall polysaccharides of several strains of enterobacteriaceae and the AB
oligosaccharides of human erythrocytes are structurally similar.
3. Newborn babies of blood groups A, B, or O do not have either anti-A or anti-B isohemagglutinins, but will
develop them during the first months of life, as they get exposed to common bacteria with
polysaccharide capsules. However, newborns are tolerant to their own blood group substance, so
they will only make antibodies against the blood group substance that they do not express. Blood group
AB individuals never produce AB isoagglutinins.
B. Other Mechanisms for the Generation of Natural Antibodies.
Cross-reaction is probably the most common explanation for the emergence of “natural” antibodies, but other
mechanisms, such as the mitogenic effects of Tindependent antigens and the nonspecific stimulatory
effects of lymphokines released by antigen-stimulated T Lymphocytes, which could activate B cells
responding to other antigens, could explain the rise of “nonspecific “Immunoglobulin’s that is observed
in the early stages of the humoral response to many different antigens.
C. The Significance of “Natural” Antibodies. “Natural” antibodies may play an important protective role,. It
is logical to assume that such cross-immunizations may be rather common and play an important
protective role against a variety of infectious agents.
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2.
Non-inducable Nonspecific Responses:
Include the following:
1. Physical and Chemical Barriers:
Including the integrity of the epithelial and mucosal surfaces, the flow of mucosal secretions in
the respiratory tract, the acidity of the gastric contents, and the secretion of lysozyme in tears,
saliva, and most secretions. The importance of these barriers is apparent from the prevalence of
infections when their integrity is compromised.
2. Anatomic barriers
Skin mechanical barrier retards entry of microbes.
Acidic environment (pH 3–5) retards growth of microbes.
Mucous membranes normal flora competes with microbes for attachment sites and nutrients.
Mucus entraps foreign microorganisms.
Cilia propel microorganisms out of body.
Examples of non-specific defiance mechanism
Site
Protective products
Skin
fatty acid secretions
Oral cavity
Enzymes & Abs in saliva
Respiratory system
hair in nasal passage, enzyme, Abs
Gastric system
low pH of stomach, enzymes and Abs in secretion
Eyes
Lysozyme
Genitourinary system
low PH
Stages in Phagocytosis
Stage
Event
Mechanism
1
Movement of phagocyte towards the
microbe
Chemotactic signals e.g.Muramyl dipeptide (MDP).
complement
2
phagocyte Attachment to the phagocyte
surface
Sugar e.g. mannose ,complement and Fc receptors
3
Endocytosis of microbe resulting in a
phagosome
Invagination of surface membrane
4
Fussion of
alysosome
Microtubules involved
5
Killing of microbe
the
phagosome
with
a-
Oxygen dependent killing e.g. O2 radicals.
b-
Oxygen independent e.g. Myeloperox.nitric
oxide.
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Resistance Mechanism
Types of resistance
Example
Non specific(innate ) :
Skin and mucous memb,mucous coat
(glycol,proteogly ,lysozymes),shedding
of cells , flushing action.
Mechanical
Chemical
Physiological
Body temp., O2, hormonal, age, ethnic
group, species microflora.
The inflammatory process.
Specific (acquired)
Naturally (acquired)
Artificially (acquired)
Placental transfer (passive) recovery from
disease (active).
Administration of antitoxins (passive) .
Vaccination(active)
Comparative between Innate and acquired immunity
Characteristics
immunity(innate)
Responds rapidly
Cells
Phagocyted (PMN)
& Dentritic cells macrophage
No or some specificity
Complement
Molecules
Cytokines
Acute phase proteins
No memory
Adaptive immunity
T and B cells
Antibodies& cytokines
Slow to start
Highly specific
Memory
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