Exam2 Flashcards
Describe Type I HS. What mediates it? What sequence of events?
Mediated by mast cells that have been activated by crosslinked IgE bound to Fc receptors.
DC takes allergen to LN, activates Th2 cells to produce IL-4, IL-4 helps B cells class switch and produce IgE.
On second exposure antigen crosslinks IgE on mast cells
Describe the immediate phase of T1HS
- minutes after exposure
- release histamine, prostaglandins and leukotrienes (lipids), preformed cytokines and chemokines
- increase in vascular permiablity and contration of smooth muscle
- tissue swelling and bronchoconstriction
Describe the late phase of T1HS
- first seen 2-4hours after exposure, actually 8-24 hours later
- Th2 cells to site, release IL-4 to get B cells to produce IgE
- release IL-5 to recruit eosinophils, also TNF
- get second phase of smooth muscle contraction, sustained edema and tissue remodeling, expansion of edema
mmunologic basis for therapeutic strategies for the treatment of allergy.
a. Anaphylaxis- treat with epinephrine, beta2 adrenergic agonist- causes smooth muscle cell contraction, increases cardiac output to counter shock, and inhibits bronchial smooth muscle cell contraction (BRONCHIAL RELAXATION)
b. Bronchial asthma- corticosteroids- reduce inflammation by inhibiting histamine and cytokines (TNF, IL4 IL5)
i. Leukotriene anatagonists- relax bronchial smooth muscle and reduce inflammation
ii. Phosphodiesterase inhbitors- relax bronchial smooth muscle
c. Other allergic diseases- desensitization of low doses of antigen- may inhibit IgE production
i. Anti-IgE antibody- omalizumab- neutralizes and eliminates IgE
ii. Antihistamine- blocks action of histamine on vessels and smooth muscle
iii. Cromylon- inhibits mast cell degranulation, inhibits leukotrienes and PAF, prevents bronchial constriction
d. In clinical trials:
i. Block Th2 activation- by induction of Treg cells and stim Th1 response
ii. Block B cell activation to IgE production- block co-stim CD40L or inhibit IL-4 or 13
iii. Block mast cell activation- block IgE receptor
iv. Block eosinophil dependent inflammation- inhibit IL-5 or CCR3
Be able to identify the different cell types and mediators and understand the mechanisms of the immediate hypersensitivity response.
a. Type I hypersensastivity requires an initial sensatizaiton and then reexposure
i. Sensatization- IgE antibody production
1. APC (DC) process and present allergen antigen to naïve T cells in the lymph node causing activation/differentiation of Th2 cells.
2. Th2 cells secrete IL-4 which allows B cells to class switch and produce IgE instead of IgM, this takes days to week but now primed for allergy
ii. Re-exposure- mast cell activation via crosslinking
1. Allergen specific IgE binds to FcERI on mast cells- binding is stable, on second exposure already have mast cells bound to IgE
2. Allergens cross-link allergen specific IgE antibodies specific for the allergen on the mast cell membranes.
3. Antigen binding to IgE already bound by the FcREI receptor on mast cells causes crosslinking of the bound IgE and aggregation of underlying FcREI causing degranulation of mast cell mediators.
4. People with allergies do not have more IgE bound, they have more IgE that will react with a specific allergen/antigen.
Understand the differences between the 4 types of hypersensitivities, and be able to provide an example of a non-autoimmune related hypersensitivity reaction mediated by each of the different types of hypersensitivities.
a. Type I hypersensitivity- immediate hypersensitivity, allergic or atopy, IgE activation of mast cells produces an inflammatory reaction
b. cross-linked IgE antibody bound to Fc receptors activating mast cell and their mediators.
i. Ex: allergic rhinitis, asthma, systemic anaphylaxis
ii. Occurs within minutes of second exposure to antigen
iii. Allergen causes- increased vascular permeability, vasodilation, bronchial and visceral smooth muscle contraction, and local inflammation
c. Type II hypersensitivity- antibody dependent cytotoxic reactions, mediated by compliment, FcR+ cells-phagocytes and NK cells
i. Complement dependent reaction
1. IgM mediated lysis- IgM ab is directed against antigen on CELL MEMBRANE, activates compliment, lysis via MAC
a. Ex: ABO mismatch,
2. IgG mediated lysis-IgG attaches to basement membrane or matrix and activates compliment, C5a is produced which recruits neutrophils and monocytes to activation site, release of enzymes and ROS causes tissue damage
a. Ex: penicillin high dose, goodpasteur, rhematic fever
d. Type III hypersensitivity- immunocomplex hypersensitivity
i. Second exposure of antigen causes antigen-ab complexes to form and deposit in vasculature, complement is activated and attracts neutrophils that damage tissue.
ii. Can be from immune response to anti-serum from foreign soruce (like horse) or foregin materials (some viruses)
iii. Ex: arthrus reaction (farmer’s lung) and serum sickness
e. Type IV hypersensitivity- ANTIBODY INDEPENDENT T cell mediated reaction
i. DRH- CD4 Th1 cells activate macrophages- leads to cytokine tissue damage ex: TB reaction, contact dermitis.
ii. CTL- CD8 cells react with MHC I antigens causing cell lysis, contact dermitis
Describe the importance of FcREI receptor on mast cells
- has high affinity, all receptors are bound in normal and allergic patients
- must be cross-linked with allergen for activation
- allergic patients bind more IgE with SAME ANTIGEN SPECIFICITY
- on mast cell, basophils, eosinophils
understand the general concepts of self-tolerance and tolerance.
a. Tolerance/immunoregulation- nautral mechanisms that eliminate or control autoreactive lymphocytes and prevent autoimmune disease. May contribute to to the failure to develop immunity against tumors in cancer patients or protective immunity against disease.
b. Antigen specificity is random so many self reactive cells are generated so must control or eliminate. Self tolerance is a state in which the adaptive immune response does not react destructively against the host. Autoimmunity= loss of self tolerance.
understand the immunological basis of Central Tolerance.
a. Central tolerance- elimination of majority of self-reactive T cells through negative selection in the thymus, T cells with high affinity receptors are eliminated or induced to become T reg cells.
i. Can only eliminate T cells that express receptors specific for self peptides that are expressed or presented in the thymus, expression of self peptides in the thymus= AIRE gene
b. Self reactive peptides with LOW AFFINITY or do not encounter self peptide in the thymus can escape to the periphery. Could possible start autoimmunity but in normal people- count on peripheral tolerance
understand and be able to describe the immunological processes responsible for the various components/mechanisms of Peripheral Tolerance.
a. Peripheral tolerance- the mechanisms that control the autoreactive T cells that escape negative selection in the thymus and move to the periphery
i. Immunological ignorance- most effective, some antigens can be physically (blood testes barrier) or immunologically (non functional APC) be sequestered from lymphocytes. Or just in low quanities in periphery and are ignored by T cells
ii. Immune privelge- places where allogenic grafts are not rejected (eye, testes, brain) because they are highly susceptible to inflammatory damage. Have evolved to downreg immune response and are anti inflammatory. Mechanisms:
1. Selective barrier to immune cells
2. Immunosuppressive milieu (high levels TGFbeta-immunosuppresive)
3. Constituitive expression of apoptosis inducing molecules- FasL will destroy Fas expressing T cells
iii. Anergy- permanent unresponsiveness induced by signaling through the TCR in absence of costimulator (CD28)
iv. Inhibitory signaling- CTLA4 binds to B7 on APC better than CD28 costim from T cell does. Blocks T cell activation. Also activates T reg cells
1. PD-1 is expressed by T cells and binds to APC expressed PDL1 or 2 to block T cell activation, not killing it
v. Peripheral deletion- induce apoptosis to constrict T cells after elimination of pathogen or persistent antigen stim.
1. Antigen is defeated, reduce IL-2, T cells begin to die
2. AICD- activated-induced cell death is death receptor dependent. Is induced by activated T cells through Fas/FasL in response to persistent stimulation by antigen
vi. Immune deviation- deviation from a Th1 to Th2 response or vice versa
1. Th2 cytokines suppress Th1- IL-4, IL-10, TGFB
2. Th1 cytokines suppress Th2- INFgamma
vii. Active immune suppression- T reg cell suppression of immune system
understand the differences in the factors/conditions that govern immunogenicity versus tolerogenicity to protein antigens.
a. Tolerance- high doses, prolonged, IV oral or nasal presence in generative organs, antigens without adjuvants (costims), low costims or cytokines
b. Immunogencity- varying does, short lived, subcut intradermal absent in generative organs, co-stims or adjuvants to stim T helper cells, high levels of co-stimulators
understand the immunological basis for B cell tolerance.
a. Central B cell tolerance- immature B cells in bone marrow encounter multivalent self antigen (MHC)
i. Negative selection- death through apoptosis, clonal deletion
ii. Receptor editing- maturation is arrested, RAG if presenet rearranges light chain DNA and creates a new specificity that is not self-reactive
b. If encounter monovalent self antigen- results in angergy of self-reactive B cell. Will go to periphery but does not get co-stim
c. Immature low affinity self reactive B cells can migrate to T cells in peripheral lymphoid organ but differentiation is arrested if self-antigen is encountered in T cell zone without self-reactive T cell. T cell tolerance is important to maintaining B cell tolerance.
Describe the role of Treg cells
They are Cd4/25 cells. CD25 surface marker is always on and activated by CTLA4. Need Foxp3 to function. Can suppress most immune cells.
Learn various transplantation terminologies
a. Autologous graft- into same person
b. Isograft/syngeneic graft- into an identical twin
c. Allograft- between two people of same species
d. Xenograft- between different species
e. Orthotopic graft- normal site in recipient as in host
f. Herterotopic graft- different site in recipient as in host
Compare direct and indirect recognition of alloantigens at the cellular and molecular level.
a. • Direct allorecognition. Most tissues contain dendritic cells, and when the tissues are transplanted, the dendritic cells are carried in the graft. When T cells in the recipient recognize donor allogeneic MHC molecules on graft dendritic cells, the T cells are activated; this process is called direct recognition (or direct presentation) of alloantigens. Direct recognition stimulates the development of alloreactive T cells (e.g., CTLs) that recognize and attack the cells of the graft.
b. • Indirect allorecognition. If graft cells (or alloantigens) are ingested by recipient dendritic cells, donor alloantigens are processed and presented by the self MHC molecules on recipient APCs. This process is called indirect recognition (or indirect presentation) and is similar to the cross-presentation of tumor antigens discussed earlier. If alloreactive CTLs are induced by the indirect pathway, these CTLs are specific for donor alloantigens displayed by the recipient’s self MHC molecules on the recipient’s APCs, so they cannot recognize and kill cells in the graft (which, of course, express donor MHC molecules). When graft alloantigens are recognized by the indirect pathway, the subsequent rejection of the graft likely is mediated mainly by alloreactive CD4 + T cells. These T cells may enter the graft together with host APCs, recognize graft antigens that are picked up and displayed by these APCs, and secrete cytokines that injure the graft by an inflammatory reaction.
Distinguish how direct and indirect recognition of graft alloantigens elicit activation of host T cells in draining LN.
a. Direct alloantigen recognition occurs when T cells bind directly to intact allogeneic major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs) in a graft, as illustrated in Figure 10-8 . B, Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up and processed by recipient APCs, and peptide fragments of the allogeneic MHC molecules are presented by recipient (self) MHC molecules. Recipient APCs also may process and present graft proteins other than allogeneic MHC molecules.
Relate the different types of rejection to the immune response elicited
a. The direct pathway may be most important for CTL-mediated acute rejection, and the indirect pathway may play a greater role in chronic rejection, as described later.
b. • Hyperacute rejection occurs within minutes of transplantation and is characterized by thrombosis of graft vessels and ischemic necrosis of the graft. Hyperacute rejection is mediated by circulating antibodies that are specific for antigens on graft endothelial cells and that are present before transplantation. These preformed antibodies may be natural IgM antibodies specific for blood group antigens, or they may be antibodies specific for allogeneic MHC molecules that are induced by exposure to allogeneic cells due to previous blood transfusions, pregnancy, or organ transplantation. Almost immediately after transplantation, the antibodies bind to antigens on the graft vascular endothelium and activate the complement and clotting systems, leading to injury to the endothelium and thrombus formation. Hyperacute rejection is not a common problem in clinical transplantation, because every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor. (The test for antibodies is called a cross-match.) However, hyperacute rejection is the major barrier to xenotransplantation, as discussed later.
c. • Acute rejection occurs within days or weeks after transplantation and is the principal cause of early graft failure. Acute rejection is mediated by T cells and antibodies specific for alloantigens in the graft. The T cells may be CD8 + CTLs that directly destroy graft cells or CD4 + cells that secrete cytokines and induce inflammation, which destroys the graft. T cells may also react against cells in graft vessels, leading to vascular damage. Antibodies contribute especially to the vascular component of acute rejection. Antibody-mediated injury to graft vessels is caused mainly by complement activation by the classical pathway. Current immunosuppressive therapy is designed mainly to prevent and reduce acute rejection by blocking the activation of alloreactive T cells.
d. • Chronic rejection is an indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function. Chronic rejection may be manifested as fibrosis of the graft and by gradual narrowing of graft blood vessels, called graft arteriosclerosis. In both lesions, the culprits are believed to be T cells that react against graft alloantigens and secrete cytokines, which stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft. Alloantibodies also contribute to chronic rejection. Although treatments to prevent or curtail acute rejection have steadily improved, leading to better 1-year survival of transplants, chronic rejection is refractory to most of these therapies and is becoming the principal cause of graft failure.
How can you prevent graft rejection
- match ABO antigens
- test recipient for preformed antibodies recognizing alloantigens from donor
- limit HLA/MHC mismatch
- corticosteroids, deplete T cells, block co sim (CD28-B7), inhibit IL-2
- mixed chimerism- introduce donor hemopoetic elements to recipient
what is the main limitation to bone marrow transplatation
graft versus host disease
Describe GVHD. How can you reduce the likelihood of happening
Grafted mature T cells reacting to alloantigens in the recipient. It is directed against minor antigens. Eliminating T cells before BM transplant can reduce GVHD
Compare acute and chronic GVHD
Acute GVHD- within weeks (up to ninety days?), epithelial cell death in skin liver gut with rash jaundice diarrhea and gut hemorrhage. Intiated by T cells in BM, then NK cells and CTL and cytokines damage tissue.
Acute GVH (Fig. 4-10)
a. Donor CD8 cytotoxic T cells recognize host tissue as foreign, proliferate in the host tissue, and produce severe organ damage.
• Type IV cytotoxic T cell HSR
Chronic GVHD- characterized by FIBROSIS and organ atrophy (lung, liver, gut). If severe leads to organ failure
How do you prep for a BM transplant?
MUST GET COMPLETE HLA MATCH- usually a sibling
radiation/chemo to deplete marrow cells and vacate site and suppress immune system
Describe Hyperacute transplant reaction
Hyperacute rejection (Fig. 4-9A)
a. Definition—irreversible reaction that occurs within minutes or hours after
transplantation
b. Pathogenesis of hyperacute rejection
(1) Type II HSR involving immunoglobulin and complement that targets the endothelium of small vessels (e.g., arterioles, capillaries), which causes a neutrophilic infiltrate with fibrinoid necrosis and vessel thrombosis, leading to infarction
• Since the reaction is irreversible, the organ must be removed.
(2) Causes of hyperacute rejections include:
(a) ABO incompatibility (e.g., blood group A person inadvertently receives a kidney
from a blood group B person)
(b) Reaction between preformed anti-HLA antibodies in the recipient directed
against similar donor HLA antigens located in the vascular endothelium
(3) These reactions are uncommon because of pretransplantation screening (see later).
What are the risk factors for developing food allergies
- Eczema and egg allergy for peanuts, particularly FLG mutation leading to eczema. Eczema- food allergy- rhinitis- asthma (the march)
- Family history
- Males more affected than females
- urbanized countries
- family that eats more peanuts greater risk of peanut allergy from cutaenous exposure
- C section 7 times higher risk for egg, fish, nut allergy
- low gut bacteria flora diversity
What mechanism mediates food allergies
T1HS. APC takes allergen to draining lymph node to naive T cell. T cells become Th2 cell. Th2 response produces IL-4 and IL-5, also 6 10 13. Mediates antibody mediated immunity and allergies and asthma
Describe some symptoms of anaylaphalaxis
Mediated by histamine, increase mucous, redness, dilate systemic blood vessels, contract bronchi, hypotension, eosinophil infiltration, itching
3 major criteria: 1) acute cutaneous hives and swelling and either respiratory or cardiovascular sx
2) acute onset of 2 organ systems- cutaenous, respiratory, GI, cardiovascular
3) acute hypotension
What are the most common symptoms of anaphylaxis
1) hives of skin 2) swelling of skin
Then respiratory and GI problems
How do we test for allergies?
Skin test gives reaction without systemic reaction.
In vitro allergen specific IgE tests:
- RAST test- radiolabeled anti-IgE antibody to detect IgE antibodies bound to allergen. Old way
- ELISA- measures in vitro allergen specific IgE in blood. Current test used
Explain the hygiene hypothesis
Germ free mice show tendency toward Th2 cells instead of Treg cells mediated by Foxp3. Think that the more bacterial diversity in the gut the lower allergic sensativity by increasing the threshold for reactivity. Antibiotics increase allergy but microbilal compound (CpG) inhibit IgE.
What is the dual allergen exposure hypothesis
- If exposed to allergen through skin, mediate Th2 memory cells and Pro allergenic
- If exposed to allegen through GI tract orally, mediate Th1 and Treg memory cells and pro-tolerance
Describe the LEAP study in food allergies
Tried to find out when to introduce allergenic foods. Split into skin test negative and skin test positive (slight positive, big reaction thrown out) then split into peanut avoidance and peanut consumption. Found consumption groups had 81% reduction in peanut allergy at 5yo. Leap on trial showed the changes were permanent.
Describe the EAT study in food allergies. What about egg study?
Introduced allergenic foods at 3 months of age vs just breastfeeding. Took all kids not just high risk. The group that followed protocol and consumed allergenic foods at 3 months had less allergies at 3yo.
However different study found that a decent amount of infants at 4 months already had an egg allergy
What are the current advice for feeding/introducing kids allergenic foods
1) high risk kids (eczema and egg allergy) should get peanut at 4-6 months old
2) High risk patients should be tested before introduction. 0.35 or greater to allergist first
3) infants without a risk factor get peanuts whenever appropiate
Describe the benefits of probiotics/prebiotics in food allergies
-Probiotics- intestinal bacteria that may have health benefits. Lactobacillus, bifido, propioni…
Prebiotic- sugar that stim bacteria growth.
Pregnant women given pro and prebiotics gave birth to less eczema kids. Lactobacillus maybe be better than bifido.
Posnatal is too late but may help C section babies more. High risk infants with prebiotics reduced eczema
Describe some recipient safety measure in blood transfusions
Permanent donor deferral- HBV, HCV, HIV, dura matter or HgH received (CJD risk), insulin from beef in UK (vCJD risk).
12 month deferral- exposure to Hepatitis, jail for 72 hours, skin puncture, malaria travel, high HIV risk, time in UK
Describe indications and contradictions to WB transfusion
Indicated: to increase O2 capacity and volume expansion. Actively bleeding or lost 25% of blood volume. Increase Hb by 1 and Hct 3% for one unit. MUST be ABO identical
Contradicted: if not need volume or O2 up. Not for platelets, granulocytes, or plasma replacement. Not in chronic anemia.
Describe packed RBC transfusion. When used and when not? What does it contain?
Contains reduced plasma, WBC and platelet. Not platelets or granulocytes.
Indicated: symptomatic anemia, increase in O2 without volume expansion. ABO compatible. Increase 1 Hb and 3% Hct
Describe WB derived platelets vs. apharesis platelets.
WB platelets- increases platelets by 5-10k for a unit, give 4-6 units to increase 30-60k.
Apharesis platelets- increase platelets by 30-60k per unit.
Indications: thrombocytopenia and platelet dysfunction to prevent bleeding
Contradictions: TTP, HIT, ITP
If give platelets and see no increase in platelet count, what is happening?
Patient is in either bleeding or has abs to platelets or HLA abs. Should give crossmatched or HLA matched platelets.
Usually ABO matched platelets given
Describe granulocyte transfusion.
Should be administered ASAP after collection. Used when patient has neutropenia or infection not responding to antibiotics or tx. Red cell compability must be tested first.
