What are the different barriers of the first line of defense of local immunity?
- Anatomic barriers: epithelium
- Physiologic barriers: body temp, pH, normal microflora, organ motility, chemical mediators
What are examples of how epithelium is an anatomic barrier in the first line of defense?
- skin: keratinized stratum corneum
- mucous membranes: secretions "wash away" microbes and cilia "sweep away" microbes
What are some chemical mediators of physiologic barriers in the first line of defense?
- defensins: directly kills microbes (secreted by epithelial cells)
- hydrolytic enzymes
What are some examples of first line of defense barriers(both anatomic and physiologic)?
- Intestine: resident microflora keep pH and oxygen tension low while intestinal epithelial cells secrete alpha defensins, paneth cells.
- Respiratoty system: filtering of microbes through nose, coughing, mucous and by particle size.
What acts as the second line of defense of local immunity?
- Surface antibodies
- Intraepithelial and mucosal lymphoid tissue
- Intraepithelial phagocytes
What surface antibody is the most important in the second line of immunity defense?
What is the role and function of the surface antibody, IgA, in the second line of defense?
- Neutralizes agent and prevents it from invading
- Secreted by mucosal plasma cells
- Actively transported to mucosal surface via specialized receptors, plgR, and vesicles
- Unique in ability to act in three locations: tissue fluid, intracellular, mucosal lumen
- Some goes to liver; also may go to systemic circulation and other mucosal sites.
What is special about plgR receptors?
- plgR transports IgA to mucosal surface after it is secreted by mucosal plasma cells.
- Then it is cleaved
- A part of it remains with the IgA and protects IgA from digestion (secretory component)
What are other surface anitbodies besides IgA and what do they do?
- IgM, IgE, IgG
- They destroy antigen within tissues
- IgM is the earliest immunoglobulin found in the intestine of the newborn.
What other antibody can bind to specialized receptors plgR?
IgM can also bind to plgR and be transferred to the intesinal lumen, but it is more susceptible to digestion since it does not remain with IgM once plgR is cleaved like it does when transporting IgA.
Mucosal surfaces and sub-epithelial areas contain large amounts of _________________.
Mucosal lyphoid tissues fall into what 2 groups?
- induction sites
- effector sites
What are induction sites?
A group of mucosal lymphoid tissue where antigens are initially encountered, processed and immune responses are initiated.
What possess all components required to initiate immune responses of induction sites?
- Mucosal associated lymphoid tissue (MALT): T cells, B cells, dendritic cells
- Found in nasal mucosa (NALT), conjunctivae, tonsils, pharynx, tongue, palate
What is GALT?
Gut associated lymphoid tissue (GALT): peyer's patches, lymphocytes in lamina propria
What is BALT?
Bronchial associated lymphoid tissue (BALT): lungs, airways
What are effector sites?
- Mucosal lymphoid tissue where antibodies and cell mediated responses are generated.
- Antigen and/or APCs leave the induction sites and enter the draining lyphatics and/or blood.
- Migrate to other locations: lung, mammary gland, other parts of the gut.
- These locations become effector sites→
activated cells are now ready to protect.
Why is important for there to be migration of antibodies to multiple sites?
The entire migration process ensures that multiple mucosal sites are protected even if an antigen is initially encountered at only one place. It is also critical for transfer of maternal antibodies into milk.
What are the intraepithelial phagocytes?
- Dendritic cells: send up dendrites between cells and samples from the surface.
- M cells: take up microbes and pass them directly to other cells.
- Alveolar macrophages: technically these are "surface" cells
- Surface lymphocytes: gamma/delta CD4 cells, some CD8 cells
What does the third line of local immunity defense consist of?
- These are barriers encountered by an antigen that penetrates the first line, the mucosa, and evades the second line, IgA.
- subepithelial antibodies
- subepithelia innate and adaptive immune cells
What are the subepithelial anitbodies?
IgE: attached to subepithelial mast cells
Cross linking produces degranulation which increases vasoactive factors, circulation, and organ motility.
What are the subepithelial innate and adaptive immune cells?
- Mast cells
- Phagocytes: dendritic cells, neutrophis, macrophages
- lymphocytes: plasma cells, CD4 lymphocytes, CD8 lymphocytes
What are Coombs and Gell's classifications of hypersensitivity?
- Type I: immediate hypersensitivity, IgE degranulation of mast cells and/or basophils
- Type II: antibody mediated (other than IgE) against self
- Type III: immune complexes; aka arthus reaction
- Type IV: delayed hypersensitivity, cell-mediated
What type of hypersensitivity involves interation of antigens with cell-bound IgE on mast cells or basophils while cross linking of this surface IgE induces activation and degranulation of the cells?
Type I hypersensitivity
When mast cells degranulate with Type I hypersensitivity, what different mediators do the release?
- Histamine and other mediators: pruritus
- Cytokines: IL-4, IL-5, IL-13-favors Th2 based inflammation
- Vasoactive molecules: whealing and edema, increases circulation to area and brings in other cells and mediators
- Smooth muscle constriction: increased organ motility leads to expulsion of antigens, may be excessive - dyspnea
What is an allergen?
antigens that stimulate allergies
When does Type I hypersensitivity occur?
- Occurs within seconds to minutes after antigen exposure
- May also have a "late phase" at 6-24 hours
What happens if excessive allergies occur?
- May produce life threatening systemic response: anaphylaxix
- Severe system wide circulatory collapse and dyspnea leading to death
Some substances can induce mast cell degranulation in the absence of ________, producing ________________ reactions.
Most animals respond to environmental antigens in beneficial ways, including by the production of IgG and IgA but some animals are predisposed to Type I hypersensitivity how?
Some animals mount an exaggerated Th2 biased response and produce excessive IgE: atopy, atopic
Subsequent exposures to allergen produce clinical signs. Why is that clinical allergy (usually) does NOT occur on first exposure?
- Because it takes time for allergen specific B cells to become activated and undergo isotype switching to IgE. This takes a few weeks.
- Exception: if you are exposed to an antigen that is very similar (cross-reactive) to one to which you were previously sensitized.
What are some clinical Type I hypersensitivity syndromes?
- atopic dermatitis: itching,predisposition to secondary infections
- urticaria: development of welts(aka wheals or hives)
- asthma: bronchoconstriction, dyspnea
- allergic conjunctivitis and rhinitis
- food allergies: may present with gastrointestinal, cutaneous or respiratory signs
How is Type I hypersensitivity diagnosed?
- passive cutaneous anaphylaxis: almost never used in clincal medicine
- intradermal allergy testing: most commonly used
- evaluation of serum IgE levels
What is passive cutaneous anaphylaxis?
Diagnostic testing where serum from a suspected allergic patient is injected into the skin of a normal patient. The normal patient is then challenged with the suspected allergen. The injected areas of skin are then observed for the development of a wheal. Almost never used in clinical medicine.
What is intradermal allergy testing?
Diagnostic testing where suspected allergens are injected into the dermis, observe the injected areas for the development of a wheal. Most commonly used technique.
What dianostic tests evaluate the serum IgE levels?
- ELISA(enzyme linked immunosorbent assay)
- RAST(radioallergosorbent test)
- Western blotting
- These detect allergen specific IgE in the patient's serum
How is Type I hypersensitivity treated?
- Avoid allergens, when practical
- Allergen specific immunotherapy, aka desensitization: attempt to induce tolerance to the offending allergen
- Anti-inflammatory medications
Describe Type II hypersensitivity.
- antibody mediated, directed against "self" antigens (true autoimmunity)
- directed against foreign antigens that bind to your own cells (e.g. drugs)
- potentially directed against "foreign" cells that are administered to you (e.g. blood transusion)
- regardless of the target, antibodies induce destruction of the cells
With Type II, antigens that are expressed on the surface of RBC are called _______________________.
blood group antigens
With Type II, Some blood antigens cross react with some glycoprotein PAMPs causing what?
Causing them to be targeted by pre-existing antibodies. This is an example of how a hypersensitivity can occur even if you have never been exposed to an agent before.
With Type II, most transusion reactions occur when the recipient's antibodies react against the donor's RBC, however, it is possible for the donor to have large amounts of antibodies that would react to the recipient's RBC. How can transfusion reactions be minimized?
- By testing the recipient to ensure that they do not have pre-existing antibodies against the donor RBC: major cross matching.
- If large amounts of whole blood are to be transfused, its also prudent to check to make sure that the donor doesn't have anti-recipient antibodies: minor cross matching.
Describe the Type II hypersensitivity, neonatal isoerythrolysis.
- Females can become sesitized to foreign RBC by prior transfustions, or to fetal RBC during a pregnancy.
- Fetal RBC can leak into the maternal blood.
- This induces the development of anti-RBC antibodies, which then can be transferred to the colostrum.
- The foal absorbs these antibodies and develops rapid hemolysis
Describe the Type II hypersensitivity, immune mediated hemolytic anemia.
- Often related to the development of "anti-self" antibodies.
- May also occur when antibodies develop against foreign proteins that are adhered to self RBC--certain drugs and infectious agents can do this
- Regardless of the exact target of the antibody, the RBC are attacked and destroyed
Describe Type III hypersensitivity.
- Immune complex hypersensitivity.
- Large complexes of antibody bound to antigen
- In this case, the whole structure gets out of control and huge.
- Occurs especially when the amounts of both antigen and antibody are very high, such as with chronic or severe infections.
- The ratio of antigen to antibody has to be just right or the huge complexes don't form-"goldilocks" phenomenon
Type III immune complex hypersensitivity is classified according to what?
The size of the complex and the site of deposition of the complex.
What are the classifications of Type III immune complex hypersensitivity?
- local reactions: generally smaller complexes, restricted to a tissue
- systemic reactions: immune complexes circulate through the bloodstream and get "caught" in tissues with fine capillary beds. This causes local activation of complement then neutrophil recruitment and then damage to tissue.
Describe Type IV hypersensitivity.
- cell mediated hypersensitivity
- certain antigens induce slowly developing inflammation at the site of antigen exposure
Describe B cell memory.
- Plasma cells develop from antigen-stimulated B cells. Plasma cells make and secrete thousands of molecules of immunoglobulins.
- Some B cells survive after a primary immune response as memory cells.
- Memory cells form a reserve of antigen-sensitive cells to be called on following subsequent exposure to an antigen.
What are the 3 types of B cells produced?
- Short-lived plasma B cells
- 2 types of memory B cells: long-lived plasma B cells and central memory B cells
Describe the life of short-lived plasma B cells.
- produced in lymphoid organs
- cells travel to the bone marrow or spleen and produce huge quantities of specific antibodies after antigen exposure.
- lives 1-2 weeks
- these antibodies provide immediate immunity to microbial pathogens.
- No Memory
What are the 2 types of memory B cells and where are they produced?
- Produced in germinal centers during invasion.
- Long-lived plasma B cells
- Central memory B cells
What are long-lived plasma B cells?
- Reside in bone marrow
- Continuously prduce a modest supply of antibodies.
- Short and long lived plasma B cells provide both immediate and long-term antibody protection.
What are central memory B cells?
- Reside mainly in the secondary lymphoid organs.
- Their job is not to produce antibodies.
- They function as memory "stem cells" which slowly proliferate and maintain the pool of central memory B cells.
- They replace those long-lived plasma cells which have died of old age.
- Can also quickly produce more short-lived plasma cells to protect from an invader attack.
What are the 2 populations of memory B cells?
- small, long-lived resting cells
- large, dividing cells
These cells, unlike plasma cells, do not have a characteristic morphology but resemble other lymphocytes. Prolonged survival does not depend on antigen contact. On exposure to antigen, they proliferate and differentiate into plasma cells.
small, long-lived resting memory B cells
These cells persists in the germinal centers. Continued survival depends on exposure to anitgen on fillicular dendritic cells. Constant low-affinity antigen binding keeps them alive.
Large, dividing memory B cells
Following T cell-dendritic cell interactions, the T cell divides ____________. The cell at the contact pole with the DC becomes helper T cell, or _________________. the cell at the opposite end of the pole becoems a ________________.
- effector T cell
- memory T cell
How can memory T cells be distinquished from naive T cells?
By their phenotype, by secrecting a different mixture of cytokines, and by their behavior.
___________________ responses are brief and cytotoxicity is seen only in the presence of antigen.
Effector T cells
Memory T cells themselves are functionally heterogeneous. What 2 types can be formed?
- Effectory memory T cells
- Central memory T cells
After naive T cells are activated (effector T cells), most of them die by apoptosis, but some of them remain in tissues. These are _________________________. They are found in inflamed tissues where they immediately attack invaders.
Memory effector T cells
During an attack, some activated T cells do not travel out to tissue to battle invaders but remain in the secondary lymphoid organs and the bone marrow. These are __________________ that can be quickly activated afte subsequent attack.
central memory T cells
Describe memory T cell survival.
- They divide more frequently than naive T cells.
- Continue to divide slowly in absence of antigen.
- Survival requires stimulation by the cytokines IL-7 and IL-15.
__________is required for both CD4 and CD8 memory T Cells.
_________is critical for the long-term survival and proliferation of CD8 T cells.
In the absence of _________and_________, memory T cells undergo apoptosis.
IL-7 and IL-15
________________cells can also develop a memory and mount a form of a secondary response to some antigens.
Natural killer cells
Natural killer cells reside where?
In lymphoid and eve nonlymphoid tissues for several months.
Unlike T and B cells, Natural killer cells employ what?
Multiple antigen receptors with distinct specificities. T and B cells express a single antigen receptor. A natural killer cell could be activated by one receptor through a different receptor.
The Natural killer "memory" response could be accurately described as what?
Training the cells rather than the cells developing specific memory.
What are the similiarities between B and T cell memory?
- Both center around stem-like central memory.
- They are more potent weapons than are naive cells.
What are the differences between B and T cell memory?
- B cells can fine-tune their receptors thru somatic mutations. T cells cannot.
- There is no T cell equivalent of the long-lived plasma B cell.
- Long-lived plasma B cells continue to produce protective antibodies, frequently for a lifetime. Antibodies continue to be deployed even after an invasion has been repulsed.
- Effector memory T cells go "dormant" as it would be very dangerous to keep them acivated and producing cytokines which are nonspecific that could cause severe damage to normal tissues.