Module 13

Parasitic Disease Map

underdeveloped equatorial countries - more parasites Climate and developed country having higher hygienic standards (better healthcare, cleaner homes) Equatorial countries have an IgE mediated response directed towards parasites that are present. In other countries we see it towards allergens, which are not pathogenic, just noxious chemicals that should have no bearing on health of organism.

Type II hypersensitivities

¡Antibodies specific for altered components of human cells §Drugs such as penicillin bind to RBCs and produce a new epitope that the immune system is not tolerant of §Results in hemolytic anemia or thrombocytopenia

Most allergens are inhaled

¡Basophils are also important here! ¡This is sensitization -inhale pollen (most common way) -stuck in mucus -allergens break down their protein antigens (always a T cell help component to get the B cell to class switch) -macrophages take it up, process, present on MHC2 -T cells are activated -TH2 make cytokines that drive B cells to class switch -In this example, the BCR recognize the same allergen. To interact with a TH2 cell it has to present MHC2 and peptide (like the macrophages). _T cell secretes IL4, driving B cell to germinal center response to class switch to IgE -Mucosal tissue has mast cells, eosinophils, basophils, IgEs immediately bind ****Sensitization phase -If phase lasts long enough, the sensitization phase can result in mast cells that can then start encountering the same allergen Mast cells then degranulate one exposure or long term exposure allergic to pets- develops when you are a child and have a pet in the family. No break in exposure of antigen, chronic exposure. Basically allergen doesn't go away with pets.

Most allergens are inhaled p2

¡Basophils are also important here! ¡This is sensitization Can invert it to something you take in to GI system, same sensitization process happens. Allergens are protein antigens (in order to get a B cell to class switch to make IgE, you have to have T help). B cell has to process and present antigen to T cells on MHC so it has to be protein. Normally proteins tend to drive TH2 reponse and prduction of IgE. Allergens are proteins, often proteases that have a function in breaking down proteins. Initiation of sensitization phase usually involves low dose of allergen. Leads to activation of CD4+ T cells. If you have ever gone through desensitization of an immune response, the desensitization phase involves injection of larger doses of the allergen. Drives a TH1 response rather than TH2, causing less class switching to IgE, ends up with B and T memory cells that are not IgE. Make more IgA and IgG, so you don't get type 1 hypersensitivity.

Chronic Asthma

¡Chronic mucus production and infiltration of leukocytes ¡Hyper-responsive airway to chemical pollutants ¡T-cell mediated response so is really also a Type IV hypersensitivity Asthmatics can have both acute asthma and chronic asthma. Acute asthma that isn't controlled means more responses take place, leading to more migration of leukocytes, meaning more leukocytes in the tissue leading to degranulation and inflammation Whole tissue remodels due to constant inflammatory response Degradation of connective tissue More cells move in Fibroblasts try to repair, proliferate like crazy Also amssive production of mucus in chronic phase, that can plug off the airway, especially the lower airways

Type IV Hypersensitivities

¡Delayed-type hypersensitivities (DTH) ¡Occur 1-3 days after contact with antigen ¡Requires much more antigen than that needed to induce Type III ¡Requires antigen presentation on MHC Class II ¡Best example is the response to tuberculin skin test- inject antigen and go back 48-72 hours later. Massive inflammatory response means you have been exposed to antigen before, in the US you have probably been infected with TB in the past. Another example- contact allergen. Nickel, pentadecacatechol in poison ivy. Usually takes 1-3 days after contact before you see T cells rush in and initate inflammatory response ALWAYS T cell mediated

Basophils

¡Express CD40 ligand (T cells express this too) §Binds to CD40 on B cells (required for activation) §Produces IL-4 and IL-13 (drive B cell to class switch too) §Combination (of T and basophil) drives the B cell to class switch to IgE Play a role in IgE class switching which can be used by cells with FcE receptors to eliminate parasite.

Type III hypersensitivities

¡Immune complexes of IgG and soluble antigen Not cell surface bound ¡Small complexes that are not removed by phagocytes ¡Accumulate in the microvasculature where they fix complement ¡Initiation of damaging inflammation Example- locally injected antigen. Large enough dose that IgGs bind to it and aggregate. Aggregate is done but the IgG can bind to another allergen and another and soon the complex is bigger and bigger. As this happens, because they are IgGs, the classical complement cascade is initiated. Complement deposition on the large aggregates (classical and alternative pathway that follow) produce anaphylatoxins. Locally at vasculature and also at mast cells, which can degranulate independent of IgE binding to allergen. IgE is all over but it has nothing to do with allergen, they are degranulating because of the C5a. Causes more inflammation and recruitment of leukocytes into the tissue.

Other Mast cell molecules: The eicosanoids (later)

¡Leukotrienes §Activity similar to histamine §100 times more potent §Latter stages of the response §similar responses as early stage -Mucus secretion, vascular permeability, smooth muscle contraction ¡Prostaglandins §Vasodilation and increased permeability §Neutrophil chemoattractant For asthmatics that respond to allergens they breathe in, there is an early response causing airway tightening. If they go untreated and recover, it takes a while for response to go away on its own due to elimination of allergen. Even if allergen goes away, several hours after there is a second asthma attack that is longer and more severe.

Eosinophil activation is highly regulated

¡Low number of eosinophils in healthy organisms because they could kill healthy bystander cells. Presence of parasite and activation of eosinophils, and the cytokines released in responses can stimulate bone marrow to make more eosinophils ¡TH2 response to infection leads to IL-5-induced production of eosinophils in the bone marrow ¡Activated endothelial cells produce a number of chemokines that call the eosinophils to the site of inflammation (where parasite may be) Eosinotaxis due to eotaxins

Allergic Rhinitis

¡Minor immediate response to allergen ¡Primarily the response to histamine release ¡Nasal edema and mucus discharge ¡Can lead to sinus infections because pathogens can enter and stay long term Allergic conjunctivitis can occur due to location of the mucus tissue and its proximity to glands in the eyes -Allergen inhaled, gets into mucosal tissue, binds to IgEs on mast cells, degranulate, end up with more leaky vasculature, more eosinophils and mucus production.

Mast Cell effector mechanisms (early)

-Antigen cross-linking IgE bound to the mast cell induces the release of granules (crosslink) §Degranulation happens immediately -Histamine binds to histamine receptors (H1 primarily) on vascular endothelial cells §Increases vascular permeability -Histamine binds H1 receptors on smooth muscle §Causes rapid smooth muscle contraction ¡Histamine binds receptors on mucosal epithelial cells (goblet cells in epithelial layer) §Increases secretion of mucus

IgE antibodies emerge at early and late times in the primary immune response

-Order of class switching in an immune response follows the order of constant regions except for IgE §IgM first, followed by IgE and IgG3. All of these have few hypermutations and they favor early complement fixation. §Later, switching to IgG1, IgG2, and IgG4 occurs. These have more hypermutations and higher affinity. §Late stages, some B cells switch to IgE but this time with more hypermutations and are the antibodies used by mast cells, basophils and activated eosinophils. Lecture: Heavy chain locus in B cells have a VDJ arrangement upstream, making variable domain. Mew and delta. Can class switch downstream to IgG, IgA, or IgE. Organization of locus looks like it is duplicated- upstream gamma, and epsilon, and alpha. Then again another upstream gamma, epsilon, and alpha. During evolution, one of the units got duplicated Gives several options to class switch to IgG, only one IgE loci is active, and another inactive gamma. 4 options for IgG, 1 for IgE, 2 for IgA. When a b cell class switches in a response to a parasite, it initially class switches downstream to IgE (harder) or upstream to IgG3 (close to mew delta). Due to transcription factors which are due to cytokines. IL4, 13, 5 open up downstream epsilon locus while also opening upstream IgG3. B cell can class switch to either. If B cell class switches to upstream gamma and becomes a memory cell, it can class switch in the germinal center during a later response. May use IgG or switch to IgE. If you clear parasite and you get it again, memory B cells can use upstream G's or class switch to IgE. Gamma can go through germinal center and switch to IgE. Affects overall number of mutations present in the VDJ, which affects affinity of antibody. In an early response, if it skips the gammas to IgE, the IgE BCR is not going to have many point mutations because it made the switch early. Some in the CDJ but it class switched, could become plasma cell, can secrete IgE with fewer point mutations. If it class switches to IgG3, makes daughter cells, then proliferate more and potentially switch to IgG1, then proliferate then switch to IgE, there are more rounds of proliferation as it goes downstream. Lot more point mutations because AID turns on when it proliferates. Later response has higher affinity.

Role of eosinophils

-Tissue resident cells with highly toxic preformed chemical mediators -Activated similar to mast cells by using Fcε receptors. IgE made for surface components of parasites are bound to Fce receptors on eosinophils on mast cells. -Main function is to kill invading parasites and microorganisms -Slow synthesis of additional cytokines, chemokines, and inflammatory mediators §Amplifies the innate response Reside in a lot of tissues Granulocytes- chemical mediators to produce toxic response to parasite (poke holes, disrupt ionic homeostasis, etc).

Other Mast cell molecules (early)

-Tryptase and chymotryptase §Enhance activity of matrix metalloproteases which are important in tissue remodeling -Allows cells to get in there ¡TNF- α §Only cell type that can store this cytokine and release it upon activation....very immediate! §Inflammation! ¡Also produce additional cytokines and chemokines upon activation....delayed response

Type 3

Also depend on the route in which the allergen comes in. If the route is intravenous (high dose, like a drug injected, or immunotherapeutic of an antibody dissimilar to humans, or toxin that is in the blood) All of them, since they are in the blood, involve blood vessel walls and microvasculature (like renal glomerulus) and joints Microvasculature of highly casculatized organs and other vascular space like joints (feeding to cartilage), deposition leads to inflammation in these tissues. Arthus reaction if it is subcutaneous and outside of vasculature If inhaled, it leads to massive deposition of complexes in the lungs, that affects function of alveoli and capillaries in the tissue, therefore affecting gas exchange. Ex: farmers lung- constant breathing in of allergens at high dose.

Chronic Asthma 2

Alveoli airway of a normal person with an allergen Alveoli is where gas exchange takes place Can see massive remodelling, lost alveoli. Ones that are there have difficult time with gas exchange due to fibroblasts and leukocytes. Actual airways are now thickened, hyperplasia of cells in the airways, tons of mucus, deposition of new connective tissue but the deposition goes from more elastic fibers to less elastic. Entire system doesn't flex the way it used to. Harder for air to get in and fewer alveoli for gas exchange.

Basophils are responsible for production of IgE

Another granular cell ¡Less than 1% of circulating WBCs Important function in mucosal tissues because they: ¡Secretes IL-4 and IL-13 at the beginning of an innate response ¡Pushes the adaptive response toward a TH2 response and production of IgE If basophils are activated in tissue where B and T cells are getting activated (ex: mucosal tissue)- then the cytokines stimulate Th2 production by activated T cells, more Th2 produces class switching to IgE

Inhaled Allergens

Asthmatic Immediate and late phase response due to transcription and translation of new proteins, even if allergen is gone. Takke B2 agonist (albuterol). Still have late phase response. Generally have to use it later in the day also.

Allergens are protein antigens, some of which resemble parasite antigens

Characteristics Allergens are often proteins (because the need for T cell response)

Allergic responses that you see (type 1) are different in different tissues. IgE mediated.

Different due to site where allergen is encountered. Allergens that stimulates it is different because they get into different systems in different ways. Food allergen- allergen enters orally. Site of allergic response is primarily in the GI system. Initially- GI type response. Get into the blood and geet into other tissues, causing hives, itching. Allergen goes through blood and ends up in capillaries in other tissues, like the skin. Can have a response from mast cells int he GI system and skin. Asthmatics- allergen, often pollen, dust mite feces, any particulate that gets into the air that can be inhaled. Airway response. Often get rhinitis too. Different pollens can stimulate rhinitis but not asthmatic responses. Allergic rhinitis- also airway, but it tends to irritate nasal mucosa and lead to rhinitis and hayfever. Wheel and flare response- Subcutaneously. Swollen region that has redness around the outside of it. Allergy testing, where they inject allergen under the skin. Systemic wide anaphylaxis is most common by allergens that get into vasculature. Often directly added- drugs, serum- to the blood. Or can have a rapid route to get to the blood, like venom injected into a person. Food allergen- GI tract is vascularized Can go everywhere, leading to system wide degranulation and inflammatory response. Can lead to death due to shock (loss of blood plasma out of vasculature) Route of entry plays major role in the type of response that we see

Type 2 hypersensitivities

Figures from lab. RBC has modified penicillin on surface, making them novel. RBC is being eliminated by macrophages due to normal mechanism (eliminates dying RBC all the time_ but modified self antigen now presented by macrophage to T cells, who have not seen the modification. T cells respond. B cells may bind to modified antigen can take it up, process, and present. Can cause them to class switch. If to IgE and it binds to RBC, it is a cell surface antigen, which is a type 2 hypersensitivity. Leads to elimination of RBC. More macrophage phagocytosis and lysis of the blood cells, leading to anemia.

Predisposition to allergic disease is influenced by genetic and environmental factors

Genetic factors for allergies #1 is MHC class 2 allele that a person has. MHC2 allotype determines peptides you present and helps direction of immune response MHC2 alleles that bind more prominently to allergens allow for response to allergens to be a TH2 response. Predisposition to allergic response. TCRa locus plays a role IL4 and IL4 receptor because IL4 signalling is important for driving TH2 response High affinity FCe receptor leads to IgEs binding to antigen more readily Having a particular type of MHC2 allotype can predispose you to better present allergen peptides leading to an allergic response

Two types of Fcε receptors

High affinity Low affinity- Doesn't look like the high affinity one. Globular head sticks away from globular surface. Long tails can be clipped by metalloproteases like ADAM10. Clips the low affinity FCe receptor, allowing it to become soluble. Binding of FCer to FC binds at different sites at high affinity vs low affinity. Both bind to FC portion of IgE. Low affinity is CD23. Interesting and unique because secretion (ie cleavage) of low affinity epsilon receptor can help drive B cells to become plasma cells, done to the B cells expressing IgE that have class switched already. Can bind to BCR that is IgE, forcing it to become a plasma cell to secrete IgE. IgE antibodies bind to high affinity FCe receptors. In people with severe allergies, we would like to prevent these IgEs to the allergens. Hard to do. But we can block the IgEs from binding to the high affinity FCe receptor, losing the mast cells that bind to IgE and degranulating.

Mast cell degranulation

Leads to a number of characteristics In GI tract- increase in secretion of fluids, muscle contractions, peristalsis, leads to diarrhea, vomiting, increased fluid to help dispel allergen. In airways- same thing, more mucus, contractions, coughing, sneezing In vasculature- inflammation leads to edema, inflammation in lots of tissues, could cause increase in lymphatic flow. Helps because it leads to moving more antigen to lymph nodes.

Mast cells are NOT B cells!

Left: normal response to parasite Right: Abnormal response to allergen BCR recognizes antigen on parasite. All receptors are identical and bind to receptor on herring worm. B cells differentiate and become plasma cell, making antibodies to this antigen. When they are IgE antibodies, they bind to high affinity FCe receptors on amst cells and eosinophils DIfference between B cells with receptors for parasite antigen vs mast cells and eosinophils that have igs hooked to them is that BCR are identical, where on a mast cell they don't have to be. Say the individual has come in contact with multiple parasites. The immune response takes place and there are plasma cells that secrete IgE antibodies to all of these things. Mast cells and eosinophils can be coated with all forms of IgE. Can be degranulated by multiple different IgEs that may respond to other things. Helps eliminate parasite, and each mast cell can be used to respond to multiple parasites. On the allergy side it is the same thing, except the receptors are not specific to parasite, they find an antigen that looks like it. Antigen binding site on anti-herring worm antibody and on anti pollen specific B cell receptor look the same in the figure. The B cell that normally would respond to antigen on a herring worm (because there is no herring worm_ responds to other antigens that look like the herring worm antigen, leading to allergic response. Antigens that we respond to allergically are similar to antigens that are present on parasites. Mast cell can have specificity to multiple things- dander, pollen, etc. Primed to degranulate when you come in contact with these allergens.

IgE-mediated allergic reactions consist of an immediate response followed by a late-phase response

Localized rapidly

Allergy is prevalent in countries where parasite infections have been eliminated

Many allergies in developed countries Hygiene hypothesis- in developed countries we have eliminated parasites (prevent children from coming in contact with dirty substances). Immune system no longer has a target. If it comes into contact with anything like it would have focused on with a parasite, it attacks it, making IgE, mast cell degranulation.

Mast Cell Granules and Mediators

Mast cells produce Type 1 response Early phase- due to preformed chemicals in the granules- things that are in red. Include enzymes that help remodel the extracellular matrix, probably because the parasite destroys extracellular matric, allowing more cells to attack parasite. Release of histamine and heparin, that are toxic to parasite and also increase the vasculature permeability and cause smooth muscle contraction. Histamine causes muscle contraction and mucus production which rids the parasite from the lungs and GI tract. TNFa in the granule of macrophages is a proinflammatory cytokine that stimulates vascular endothelium to prepare for more cells coming into vasculature. Helps stimulate more cell adhesion molecules. Slower reaction- transcriptional events create new compounds IL4, other cytokines that are important for amplification of Th2 cells, cytokines that lead to more eosinophil production, chemokines that can recruit monocytes/macrophages/neutrophils to site of infection, more lipid mediated signalling molecules that can do a lot of the things done in the early phase response Leukotrienes cause smooth muscle contraction and increase permeability and mucus secretion. More powerful than histamine.

IgE antibodies emerge at early and late times in the primary immune response p2

Mean number of somatic mutations IgE is the lowest number. As you get further away from mew delta, from proximal gamma to distal, you end up with more point mutations. B cells tend to class switch sequentially. Shows the mean Looking early in the response, IgE have very low point mutations Late in the response there are more. Depends on when they class switch with potential proliferation. Affinity of IgE matters, binds to antigen on the parasite. Higher affinity means the easier it is to hold an eosinophil next to the parasite so it can dump granules. Stuck to parasitic worm with eosinophils because of the IgE bound to FcE receptor, pointing towards parasite. High affinity IgEs bind eosinophil tighter, for more efficient dumping of granules.

Systemic anaphylaxis is caused by allergens in the blood - Type II Hypersensitivity!

Penicillin allergy can be either Type I or Type II depending on how the original TH2 response drove the B-cell class switching! Figure that shows that the same antigen can stimulate IgEl, leading to type 1 hypersensitivity response. Same sort of process, but B cell gets cytokines to switch to IgE, binds to mast cells, come in contact with RBC and degranulate. Driven by TH2 but driven by cytokines and whether it class switches to IgE or IgG.

IgE-mediated immunity and allergy

Probably evolved because of parasites

Type I Hypersensitivity Reactions

Released by eosinophils, and some basophils We will focus on mast cells ¡Results from antigen binding to antigen-specific IgE ¡IgE bound to Fcε receptors ¡Occur immediately -immediate hypersensitivity. Due to what is present in the granule when mast cell dumps them. ¡Also has a delayed component. Includes increase in transcription and translation from nucleus due to signalling from FCe receptors. Takes several hours. ¡Involves sensitization phase- had to have prior exposure to forced immune system to make IgE to make the response. Highest affinity of all Fc antibody receptors (high affinity- 1, low affinity-2) Kd of high affinity, one of the highest present≅ 10-10 M Immediately bind to IgE, why we don't see a lot of IgE in the vasculature because when it is made it is immediately bound. Binding sites on IgE point out to periphery. When mast cell binds to antigen, the signal from that binding drives mast cell to dump its granules. Happens rapidly. "immediate hypersensitivity" In a mucosal tissue- there are basophils, eosinophils, and mast cells. If those B cells, instead of class switching to IgA class switch to IgE and become plasma cells, the mast cells, basophils and eosinophils will immediately bind. That's why you don't find a lot in the blood.

Allergens are protein antigens, some of which resemble parasite antigens p2

Table to show that oftentimes allergen looks like antigen associated iwth parasite. Herring worm and types of proteins that we mount an immune response too (make IgE, drive eosinophils to kill the worms) and they look a lot like particular allergens. Systatin, typonine Common allergens mimic antigens associated with parasites. W/o parasites, immune system response is lost so it binds to things that are somewhat similar

FcεRII is a low-affinity receptor for IgE Fc regions that regulates the production of IgE by B cells

The B cell is an IgE+ B cell. B cell has already class switched. Still expresses it as a membrane bound BCR. IgA and B. Can signal if it comes in congtact with allergen or whatever the antigen is If FCe receptor 2 is present around B cell, it binds to the FC portion of the IgE and complement receptor 2, which is part of the B cell coreceptor (that includes CD19 and CD81). Complement receptor 2 binds to tail of FCe receptor 2 B cell uses ability of it to bind to complement to get additional activation signals. B cell binds to an antigen on the surface of a pathogen that has complement deposited on it, complement receptor 2 comes in and binds. Also binds to low affinity FCe receptor. Causes a crosslinking of B cell coreceptor and IgE. Causes additional signal. Drive it to become a plasma cell, secreting IgE embedded in the membrane.

Allergic Asthma

Two types: -Acute response- generally due to mast cell degranulation in mucosal tissue surrounding airway. Allergen gets in, binds to IgEs specific to it and bound to mast cell. Mast cell degranulates. Makes it more permeable, causing smooth muscle contraction and mucus in the airways. End up with lots of eosinophils driving B cells to class switch to IgE to become plasma cells. -Chronic response- lots of acute response. More acute responses you have, more recruitment times for T cells, eosinophils, more mast cells into mucosal tissue, more degranulation. Also have T helper 2 cells that come in making cytokines that activate macrophages, neutrophils, and eosinophils in the tissue, leading to influx of leukocytes into tissue and more and more tissue damage. Hyperplasia of smooth muscle cells and fibroblasts, tissue fills with T cells, eosinophils, neutrophils and macrophages. Chronic response involves T cells that make the chronic asthma response a type 4 sensitivity. ¡130 million people worldwide ¡Persistent recruitment of leukocytes into the lungs

IgE-mediated immune responses defend the body against multicellular parasites

Type 1 Function- evolved as mechanism for large parasites, can't be phagocytosed because they are so big Response to a large parasite- Example in the mucosal tissue- Response usually is triven in Th2 type of response (not always). As they are developing, more T cells differentiate into Th2 due to cytokines present in tissue. Commonly produced cytokines, IL5, IL13 are particularly important. IL4 too. Drive B cells to class switch to IgE. and IgG1 and IgG4. Also we get more eosinophils, basophils, and mast cells. Respond to pathogens (because FCe receptors can bind to IgEs). Can degranulate in response to parasite. Entire system promotes IgE mediated immune response.

Four types of hypersensitivities

Type 1-3: Immunoglobulin specific responses Type 4: due to T cells A lot of allergic reactions may have more than one type of hypersensitivity Ex: autoimmune disease with destruction of the thyroid can be type 1 and 4. Chronic asthma is 1 and 4 at the same time No hypersensitivities involve IgM, but you still may make antibodies specific to the same thing, but doesn't cause the hypersensitivity. Type 1: IgE related, always involves mast cells, release of histamine, production of leukotrienes (cause allergic rhinitis, asthma, excess mucus production, narrowing of airways, smooth muscle contraction) Type 2&3: IgG. Type 2: targets something on the surface of the cell or associated with extracellular matrix. IgGs bind on surface or matrix outside of cell. Type 3: IgG molecules target a soluble antigen, like type 1. Often in the blood. Type 4: involves T cells that can go out to site of infection (Th1, Th2, helper cells can move/migrate to site of infection, along with cytotoxic T cells) Type 1 can move from draining lymph nodes where they activate macrophages Type 2 don't do it as well, often stay in draining lymph nodes or when activated in mucosal tissue they are right there Activate eosinophils All lead to contact dermatitis, chronic asthma, chronic allergic reactions where eosinophils and T helper cells are present in large numbers in the tissue where contact is happening. Other Th1 contact related diseases- poison ivy (lab) Type 3 lead to serum sickness and arthus reaction (deposition of large complexes outside of vasculature leading to swelling, and inside vasculature leading to breaking of capallaries)

Different effector mechanisms cause four distinctive types of hypersensitivity reaction

Type 1: IgEs bind to soluble antigen. When they are secreted by plasma cells they are immediately bound to FCe receptors, so antigen binding sites point away from mast cells, just like if it was a B cell. Crosslinks, leading to degranulation of mast cell. Type 2: IgGs that bind to cell surface/extracellular matrix. Ex: penicillin modifies cell surface protein, leading to a new type of epitope that a B cell might recognize. B cell can take it in, process, present to T cells, which can help B cell, making IgG antibodies specific to that epitope. Leads to complement deposition and activation of phagocytosis by macrophages. Inflammatory response. Type 3: Soluble antigen. Ex: could be the penicillin. B cells may recognize before it modifies epitope, responding to penicillin. T cells are then activated and IgGs are made to penicillin. Start binding together with antigen. Leads to large aggregate of penicillin. Example shows species dissimilar immunoglobulin. Ex: in human system we infuse mouse antibodies (earliest immunotherapies) Problem- antibody is foreign and can activate B cell. In a T dependent manner, B cells take it in, process, present on MHC, if on class 2 T cells may recognize foreign antibody peptide and mount an immune response, leading to B cells class switching to IgG, which can bind to foreign antibodies, leading to large aggregates that get complement deposited on them, leading to macrophage and neutrophil phagocytosis and proinflammatory cytokines/chemicals are released. Due to soluble antigen. Type 4: T cell mediated event. Initially the allergen (ex: nickel modifying antigen). End up getting dendritic cells that take it up, process and present it and activate T cells in draining lymph nodes. T cells can interact with B cells, T cells are proliferating. T cells get activated and differentiate (Th1, Th2, Tfh). Some migrate back to site of infection, leading to inflammatory response. All due to T cells. They are activated that can also activate B cells that recognize whatever the nickel is bound to. B cells may get forced into germinal center and make antibodies to nickel, but they aren't going to be cause of inflammatory response, just a different component. Primarily due to T cells (Th1) and activation of macrophages, which release proinflammatory cytokines.

Systemic Anaphylaxis

When mast cells degranulate system wide, the functions are no longer local. All of thhe vasculature becomes leaky, increased permeability, swelling of tissues- tongue and back of the throat, hard to breathe, due to fluid leaking out- lower blood pressure, less oxygen, leads to anaphylactic shock. In respiratory tract- contraction of smooth muscles- harder to breathe In GI tract- contraction can lead to vomiting and diarrhea, losing fluid quickly causing dehydration. Harder for blood to transport anything. Microvasculature collapses on itself and clots off.

Treatment of allergic disease with an IgE-specific monoclonal antibody

Xolair. Binds to portion of IgE that normally binds to high affinity FcE receptor. Prevents them from binding to mast cells. Treatment over time with the antibody, as plasma cells secrete IgE, they are bound by antibody and prevented from binding to mast cells. Mast cells die out and are remade but they have a hard time binding the IgEs because Xolair is binding the IgEs. Important that the antibody binds to portion of IgE that binds to FCe receptor. If it doesn't, the antibody could cross link the IgEs that are bound to the mast cell and cause a massive inflammatory response.