Key Molecules in immune response



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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

  • Protein content

  • Size

  • Solubility

2- Dose

  • Low dose----antibody high affinity and restricted specificity

  • Moderate dose----- antibody mixed affinity and broad specificity

  • High dose ------------ tolerance

3- Route of entry

  • ID,IM,SC ------regional lymph nodes

  • IV---------------- spleen

  • Oral------------- Peyers patches

  • Inhalation----- bronchial lymphoid tissue

4- Addition of substances with synergistic effects

  • e.g. a adjuvant , other antigens

5- Genetic factors of recipient animal

  • Species differences

  • Individual differences



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.




Innate immunity ( Non specific immune response)






First line:

1) Mechanical barriers

- 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:



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)

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:


  1. 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.

    9. Oxygen potential




  1. 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.




  1. 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 = C-reactive 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 C-reactive 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.

  • Examples of Infectious Agents Able to Activate the Alternative. Pathway of complement without apparent participation of Specific antibody

  • a. Bacteria ---Streptococcus pneumonia, Staphylococcus aureus and S. epidermidis

  • b. Fungi ---- Candida albicans

  • c. Parasites - H. influenzae Type b Trypanosoma Cyclops, Schistosoma mansoni and Babesia rodhaini

  • 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.



  1. 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.

    1. 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 the phagosome with alysosome

Microtubules involved

5

Killing of microbe

  1. Oxygen dependent killing e.g. O2 radicals.

  2. Oxygen independent e.g. Myeloperox.nitric oxide.

Resistance Mechanism

Types of resistance

Example

Non specific(innate ) :

Mechanical



Skin and mucous memb,mucous coat (glycol,proteogly ,lysozymes),shedding of cells , flushing action.

Chemical




Physiological

Body temp., O2, hormonal, age, ethnic group, species microflora.

The inflammatory process.



Specific (acquired)

Naturally (acquired)

Placental transfer (passive) recovery from disease (active).

Artificially (acquired)

Administration of antitoxins (passive) .

Vaccination(active)



Comparative between Innate and acquired immunity

Characteristics

Cells

Molecules

immunity(innate)

Responds rapidly



Phagocyted (PMN)

& Dentritic cells macrophage



Cytokines


No or some specificity







Complement





Acute phase proteins

No memory








Adaptive immunity

T and B cells


Antibodies& cytokines


Slow to start







Highly specific








Memory








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