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- RESISTANCE OF THE BODY TO FOREIGN
Present form birth, nonspecific
Acquired during lifetime, directed at specific agents
Cellular and Chemical Defenses
- NK cells
- Inflammatory Response
- Antimicrobial Proteins: Interferons, Complement
Events of Phagocyte Mobilization
- 1. Neutrophils enter blood from bone marrow
- 2. Margination
- 3. Diapedesis-crossing BM
- 4. Positive chemotaxis
The Immune System
- It is antigen-specific
- It is systemic (not restricted to infection site)
- It has "memory." It recognizes and mounts even stronger attacks on previously encountered pathogens
- Granules which appear lilac in color when stained by Wright technique
- Some granules contain peroxidases, others hydrolytic enzymes, others cotain a potent mixture of antibiotic-like proteins (defensins)
- 3-6 lobed nucleus
- Often called Polymorphonuclear (PMNs)
- Neutrophils are chemically attracted to sites of inflammation and are phagocytes.
- They are especially partial to bacteria and some fungi, which they can ingest and destroy.
- Bacterial killing is promoted by a process called "respiratory burst" in which the oxygen is actively metabolized to oxidizing cmpd's (hydrogen peroxide)
- Neutrophils numbers increase explosively during acute bacterial infections such as meningitis and appendicitis.
- Bi-lobed nucleus
- Large, coarse granules that appear brick red to crimson with Wright's stain.
- These granules are elaborate lysosomes filled with a unique variety of digestive enzymes.
- Attack parasitic WORMS that are too large to be phagocytized
- Eosinophils gather around worm and release granular enzymes onto worm's surface, thus digesting it away.
- Phagocytize foreign proteins and immune (Ag-Ab) complexes involved in allergy attacks.
- Inactivate certain inflammatory chemicals released during allergic rxns.
- U shaped nucleus or S shaped with 2/3 constrictions
- Cytoplasm contains large coarse histamine-containing granules that stain purplish-black by Wright stain
- Histamine is a vasodilator that Attracts other WBCs to inflamed site
- Cells similar to basophils called MAST CELLS are found in CT
- Basophils/mast cells bind to IgE and this causes their granules to release histamines.
- Most are firmly enmeshed in lymphoid tissue
- Large nucleus that occupies most of the cell's volume
- Nucleus is usually spherical
- T lymphocytes act directly against virus-infected and tumor-infected cells.
- B lymphocytes give rise to Plasma Cells which produce antibodies.
- Largest in size of WBCs
- U or bean shaped nucleus
- Once in tissues, monocytes turn into MACROPHAGES which phagocytize pathogens of chronic infections (TB) and are crucial in the body's defense against viruses and certain intracellular microorganisms
- Any of the large, mononuclear, highly parasitic cells derived from monocytes that occur in the walls of blood vessels (adventitial cells) and in loose connective tissue (histiocytes, phagocytic reticular cells.
- Macrophages are usually immobile, but become actively mobile when stimulated by inflammation
- They also interact with lymphocytes to facilitate ab production
Recognize and destroy cells that have become infected
Diverse molecues which signal b/w lymphocytes, phagocytes, and other body cells, ex- IFNS, ILs, CSFs
Prevent spread of viruses
Have a variety of fncs, but most are involved in directly other cells to divide and differentiate.
Colony Stimulating Factors (CSFs)
Are involved in directing the division and differentiation of bone marrow stem cells and the precursors of WBCs.
- Effectors of immune response
- Messenger proteins which help in cell to cell communication
- Part of extra cellular signaling network that controls each and every fnc of the innate and specific immune response
- Autocrine-acting on same producer cell
- Paracrine- acting on nearby cells
- A group of at least 20 plasma proteins that normally circulate in the blood in an active state.
- These proteins are designated as C1-C9, and factors B, D, P.
- A major mech for destroying foreign substances in the body.
- When it is activated, chemical mediators are unleased that amplify all aspects of the inflammatory process.
- Kills many types of mircoorgs by lysis
- Complement itself is a non-specific defense mech, but it enhances both non specific and specific defenses.
- 1) Classical Pthway: depends on the binding of ab's to the invading mo and the subsequent binding of C1 to the Ag-Ab complex, a step called complement fixation.
- 2) Alternate Pthway: is commonly triggered by an interaction b/w factors B, D, P and polysaccride molecules present on the surface of certain microrg.
- Each pathway involves a cascade in which complement proteins are activated in an orderly sequence- each causing catalysis of the next step.
Complement Pthways (cont'd)
- Both pathways ultimately converge on C3, cleaving it into two fragments- C3a and C3b. This event initiates a common terminal pthway that causes mo lysis, promotes phagocytosis, and enhances inflammation.
- The final series of the pathway events begins when C3b binds to the target cell's surface, triggering the insertion of a grp of complement proteins called MAC (Membrane Attack Complex) into the cell's membrane.
- MAC forms and stabilizes an open hole in the target cell's membrane that ensures lysis by allowing solutes to leak from the cell.
- The C3b molecules that coat the mo and provides "handles" that enable the receptors of macrophages and neutrophils to adhere to and phagocytize more rapidly.
- C3a and other cleavage products produced during complement fixation amplify the inflammation response by stimulating mast cells and basophils to release histamine and attracting neurophils and other inflammatory cells to site of infection.
- Foreign substances that induce a specific immune response.
- 1) foreign to the host
- 2) MW greater than 6000 daltons , Haptens, Epitope
- Specific molecules formed in an animal's body in response to the presence of antigen. Once formed they react with a specific antigen.
- 1) Proteins containing a small amount of carb
- 2) Gamma globulin fraction of serum
- 3) Highly specific
- Composed of 4 polypeptide chains joined by disulfide bonds. Mw=150,000
- Papain splits molecule into 2 parts: Fab fragment contains the Ag combining site and Fc because it has been crystallized
- 2 major types of light chains are kappa and lambda
- Pepsin chews up the Fc piece of the molecule, but leaves the remainder of the molecule intact with its 2 ag binding sites.
- The pepsin-treated molecule is still capable of casing agglutination or precipitation rxns, but is unable to fix complement, or in the case of IgG, to pass thru the placental wall from mother to fetus.
- The Fc piece of the molecule is very important for the total normal physiological fnc of ab.
- Accounts for more than 80% of all Ig's
- Only Ig that can freely pass the placental wall
- Fixes complement
- Lyses Gram-negative bacteria
- Binds to Gram-positive bacteria
- Provides receptors for phagocytes
- Occurs in both serum and mucous secretions.
- IgA found in serum is structurally like IgG
- IgA in mucous has MW= 390,000 and is composed of 2 molecules of serum type IgA with a secretory component.
- J chain (polypeptide) links the monomeric units of IgA to form dimers
- This larger IgA is found mainly in saliva, tears, seminal fluid, in GI tract and in GU tract
- Also found in human milk
- The secretory IgA is thought to be particularly valuable as our first line of ab defense against pathgenic viruses/bacteria.
- Pathogens entering via resp system come in contact with secretory IgA first.
- Largest in size of the Ig's and is composed of 5 basic units attached to one another by way of disulfide bridges b/w their Fc pieces.
- If S-S bonds are broken, 5 subunits and a J chain are obtained
- Intact IgM molecule is composed of 10 light chains and 10 heavy chains which are antigenetically distinct
- IgM is such a compact molecule that many ag's are too large to physically fit into the 10 potential ag binding site.
- IgM usually only binds 5 molecules of ag
- First Ab to be detected, but its synthesis is not prolonged and IgG Abs are most prevalent.
- IgM Ab have a potential bactericidal effect on gram-negative bacteria in the presence of complement and are important early after infection.
- Present in serum at a level of less than 0.2% of ig's
- It is hard to purify and labile
- IgD is present on the surface of B lymphocytes and is thought to act as a cell surface receptor for Ag's, regulating the differentiation of B lymphocytes into plasma cells that synthesize Abs
- Normally only trace amounts, but found in higher amts in allergic ppl
- Involved in allergies of type I hypersensitivity
- Structurally similar to IgG, but larger
- They exist bound tightly to the surface of circulating mast cells and leukocytes.
- There are lots of mast cells in lungs and GI tract
- Igs reside in the Fc portion of the IgE molecule, and it is part of that molecule that fixes so tightly to CM
- Ppl suffering from allergies obtain relief from their symptoms by taking anti-histamines, substances that react w/ histamine before it can exert any pharmacological effect.
- Side chain is bonded to the backbone of N atom as well as the alpha Carbon.
- The resulting cyclic structure bends.
Ag binding site
- A convoluted surface that is complementary to the antigenic determinant to which it binds.
- Thus, very close fit
- Usually requires the interaction of at least 3 types of cells
- 1) B cells
- 2) T cells
- 3) APC
- T cells can recognize an antigenic determinant only when it is presented on the surface of an APC in association with a self ag
- B CELLS bind intact
- antigen to immunoglobulin receptors
- on its surface
- and then internalize
- the degrade the
- antigen before redepositing individual antigenic
- determinants back on
- the surface bound to MHC
- T CELLS can NOT interact
- with intact antigens
- and thus require
- that an antigen-presenting cell
- first process the
- antigen and then
- present it in
- a manner that
- the T cell
- can recognize. Both MACROPHAGES and DENDRITIC CELLS serve
- this function by
- internalizing an antigen
- by endocytosis, degrading it
- into smaller determinants, and then repositioning the fragments on their cell surface in association with their MHC class II compounds.
- 1) Helper T cell: help in the ag-specific activation of B cells
- 2) Delayed-typed sensitivity T cells (Tdth): involved in cell-mediated responses
- 3) Cytotoxic T cells (Tc): also involved in cell-mediated immune responses and lyse target cells by direct cell-cell contact
- 4) Suppressor T cells (Ts): down-regulate immune responses
- T cells do NOT produce Abs, nor do they have ag-specific immunoglobulins on their cell surface.
- T-independent ag's : can only induce IgM response. many capsular polsaccss are in this category.
- Insoluble materials mixed with soluble materials that act to keep the ag in tissues for much longer periods.
- ex: Aluminum hydroxide and Alu Phosphate
- cell membranes of a number of ab-ag producing spleen cells to fuse w/ myeloma cells
- can be grown in vitro, and single clones of these fused cells can be isolated and propagated to produce MONOCLONAL ABs
Ab synthesis typically involved the cooperation of three types of cells- macrophages, Th, and B cells
- 1) they differentiate into plasma cells and produce ab's, and
- 2) they can present ag to helper T cells
- During embryogenesis, B-cell precursors are recognized first in the fetal liver.
- From there they migrate to bone marrow, which is their main location during adult life.
- They do not require maturation like T cells do.
1) Selective IgA Deficiency: frequent resp infections. they have normal of B cells w/ surface IgA present
restricted to males and is characterized by recurrent bacterial infections
T- Cell Deficiencies
- Failure to develop functional thymus gland/failure of T-cell maturation
- Such ppl usually lack a cell-mediated immune system, but have functional humoral immune system cuz of small dose of helper T cells.
Severe Combined Immunodeficiency Disease (SCID)
- Complete absence of both B and T cells
- Infections affecting all exposed surfaces of body
- Most die young (bubble boy)
- 1) Oudin: A technique used to measure antigen concentration, in which an antigen and an antibody are held in an agar matrix in a test tube and allowed to diffuse toward one another.
- 2) Ouchterlony:double gel diffusion test antigen and antibody diffuse toward each other in a semisolid medium to a point in the medium where optimum concentration of each is reached. A band of precipitation occurs at this point. The qualitative Ouchterlony Test can simultaneously monitor multiple Ab-Ag system and can be used to identify particular antigens in a preparation.
- 3) Nuefeld (Quellung) Tests:The “gold standard” for epidemiological typing of Streptococcus pneumoniae(pneumococcus) is the capsular reaction test (Neufeld test) with antisera against the 90 pneumococcal polysaccharide capsules, i.e., serotyping.
- Antigens that
- exist in some,
- but not all,
- members of a
- species. e.g. , blood
- group antigens.
- Antibodies that
- exist in some,
- but not all, members
- of a species.
- e.g., anti-blood-group
- Develops in an unborn infant when the mother and baby have different blood types.
- Mother produces Ab's that attack the infants RBCs
Product that contains an Ag, consisting of killed microorgs, attenuated microorgs or toxoids
Hypersensitivity; the harmful rxn of ab with its specific ag
Increased sensitivity, or allergy, to foreign material
Type 1- HS
- Immediate HS
- Production of IgE in response to allergens such as dust mites, cat dander, or polllen
- When Ige is cross-linked by specific allergen, mediators are released
- Such as histamine, LTs, cytokines
Allergic Diseases of Type 1- HS
- Anaphylaxis, seasonal hay fever, atopic dermatitis and allergic asthma.
- Therapy: antihistamines, adrenaline, bronchodilators, corticosteroids
- Most serious HS
- Death w/in 2-3 mins
- Patient goes into "shock"
- loss of consciousness, hives, swelling of tongue
Slow-reacting substance of Anaphylaxis; it's a secondary chemical mediator
Type II - HS
- Mediated by IgG and IgM ab's binding to specific cells or tissues.
- Ab directed against cell surface or tissue ag's interact w/ complement and a variety of effector cells to bring about damage to the target cells
- Damage to tissue may be produced by ab to BMs, to intercellular adhesion molecules or receptors. such as myasthenia gravis, pemphigus, and Goodpasture's syndrome
- Inherited disorder of infants
- feeding difficulties, apnea, weakness/fatigue
- Ach receptors are destroyed!
Group of diseases characterized by bullae
- glomerulonephritis with pulmonary hemorrhage and
- circulating antibodies against basement membranes.
Type III- HS
- Ag is finely fragmented, not part of a living cell. Ab binds to this forming small ag-ab complexes. IgG + IgM
- The complexes are not removed by macrophages
- Ag-Ab complex become trapped in capillary wall
- Complement is activated
- Inflammatory cells infiltrate
- Systemic Disease. Complication of
- Serum therapy when patients were given massive doses of anti-diphtheria or
- anti-tetanus serum
- Occurs when an ag is injected into the skin of an individual who already possesses a high Ab level against the Ag.
- Ag reacts w/ IgM and IgG to form a precipitate that penetrates the blood vessels and fixes complement.
- Swelling and edema occur w/in 1-2 hrs.
- Kidneys and liver mainly affected.
- Leprosy, malaria, Dengue hemmorhagic fever, viral hepatitis.
- Kidneys, joints, arteries, skin.
- Rheumatoid arthritis
Inhalation of antigenic material
- Molds, plants, animals
- Farmer's Lungs: Moldy hay
- Pigeon Fancier's Lung: Pigeon excreta
Type IV - HS
- Delayed type of HS >12 hrs
- Persistent ag's are phagocytized and presented to lymphocytes
- Lymphocytes are activated and release cytokines
- More lymphocytes and macrophages are recruited
- Granulomatous inflammation results
Eczematous rxn at the point of contact with an allergen. Ni, Cr, poison ivy. Haptens which conjugate with body proteins. Langerhans cells in skin act as APC
Persistence of foreign agents or intracellular organisms withing macrophages
Ex of Granulomatous type
- Crohn's Disease
- 1) Migration inhibition factor (MIF): this factor acts to keep the macrophage localized in the are of inflammation.
- 2) Chemotactic factor for macrophages
- 3) Macrophage activating factor (MAF): increased phagocytic activity, increased metabolic activity, increased number of lysosomes and enzymes
- 4) Lymphotoxin: Released by lymphocytes on stimulation by the specific ag to which it was synthesized. Kills cells by interacting with the CM.
- 5) Immune Interferon: Stimulated NK cells
- 1) Autographs: tissue grafts taken from one body site and implanted to another site on the same body
- 2) Isografts: Graft donated by identical twin
- 3) Allografts: Grafts transplanted from ppl that are not genetically identical.
- 4) Xenografts: Grafts taken from another animal species
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