Allergy/Immunology Flashcards
What are the types of hypersensitivity reactions?
Type I: immediate/anaphylactic or antibody mediated
Type II: cytotoxic T cell mediated
Type III: Immune complex mediated
Type IV: delayed hypersensitivity
Anaphylaxis is a form of what type of hypersensitivity reaction?
Type I
What is the most important cytokine in the early or acute phase of at type I hypersensitivity reaction?
Histamine
What is the predominant cell type during an early or acute phase type I hypersentivity reaction?
Mast cell
What is the predominant cell type during the late phase of a type I hypersentivity reaction?
Eosinophils
In what type of hypersentivity reaction might you see a systemic hypersensitivity induced by an unknown factor that results in IgG or IgM mediated cytotoxic action against an antigen located on the surface of a cell (or compliment mediated lysis of the cell)?
Type II cytotoxic hypersensitivity
In what hypersensitivity reaction are immune complexes formed (IgG) as a result of the presence of drugs/bacterial products, which result in complement activation and a delayed (days) acute inflammatory reaction?
Type III immune complex mediated
In what hypersensitivity reaction do antigens directly stimulate T cell activation and cell mediated inflammation resulting in dermatitis, granulomatous disease and some fungal disease?
Type IV delayed hypersensitivity
What three cell types are required during the primary antigen exposure for the formation of antigen specific IgE antibody formation?
- Mast cells
- T cells (T helper cells type 2)
- B cells
Two most common causes of anaphylaxis
- Foods
- Drug reactions
A patient has multiple recurrent episodes of anaphylaxis with an unidentified cause. The patient states that his allergist asked him to have a laboratory test in the ED the next time he had an episode in an effort to confirm the diagnosis. What test does the allergist want and when should it be drawn?
Serum tryptase. Serum tryptase peaks in 30 minutes and should be drawn within 3 hours of the start of the episode
What is the most common condition to be mistaken for anaphylaxis?
- Vasodepressor reaction usually triggered by trauma or stress and manifesting as flushing, pallor, weakness, diaphoresis, hypotension and at times loss of consciousness
What dose of epinephrine should be given during anaphylaxis to adults and children?
Intramuscular administration is preferred 1ml/1ml (1:1000), mid outer thigh
- Adult 0.3-0.5mg
- Children: 0.01mg/kg, max of 0.5mg
- Can repeat at 5-15 min intervals
- Autoinjectors usually have 0.3mg for adults and 0.15mg for children who weigh less than 25kg
Primary reasons for administering an antihistamine to patients with anaphylaxis?
Resolution of cutaneous manifestations of anaphylaxis
A patient taking what kind of drugs may be refractory to the treatment of anaphylaxis?
Beta blockers
Angioedema
Significant swelling of deep dermal or subcutaneous tissues, less often associated with pruritus and more commonly associated with bruning or pain
Most common cause of angioedema?
ACE inhibitors
What is the cause of hereditary angioedema?
Caused by high levesl of CT in the bloodstream secondary to deficiency of C1 inhibitor
Mode of inheritance of heredeary angioedema
Autosomal dominant
Seasonal allergy
An outdoor allergen with seasonal occurrence. Trees in winter/spring, grasses in summer and molds in fall
Perennial allergy
Indoor allergen with no consistent seasonal pattern such as dust mites and animal dander
Intermittent allergic rhinitis
present for <4 days/week for < 4 weeks of the year
Persistent allergic rhinitis
Present for >4 days/week and more than 4 weeks of the year
Which season would you expect seasonal allergic rhinitis in response to elm, birch, ash, oak, aspen, maple, box elder, hickory, sycamore, cedar, ect
Winter/spring (Feb-May)
Which season would you expect seasonal allergic rhinitis in response to Bermuda grass, Johnson grass, sweet vernal grass, Timothy grass, Orchard grass, ect.
Late spring/summer (April-Aug)
Which season would you expect seasonal allergic rhinitis in response to ragweed, nettle, mugwort, sage, lamb’s quarter, goosefoot, sorrel, ect.
Late summer/fall (July to first hard frost)
Measures to decrease exposure to house dust mite antigen?
- Wash bedding weekly at >130F
- Use impermeable covers over pillows and bedding
- Use hardwood flooring or laminates instead of carpet
- Keep humidity levels less than 45%
How long after removing a pet from a home can it take for the amount of allergen to decrease below clinically significant levels?
4 months
A patient has asprin sensitive asthma and urticaria. In addition to NSAIDs, what chemical used in foods would you recommend they avoid?
Tartrazine (yellow #5); as many as 15% of affected individuals will react to this
Infection with what pathogenic organism is most commonly associated with eosinophilia and urticaria?
Helminth infections such as Ascaris lumbricoides
What is cold urticaria and what should patients be warned to avoid?
Rapid swelling, erythema, and pruritus after exposure to cold objects or weather. It affects only areas exposed to cold. There have been reports of death secondary to hypotension in people who swam in cold water.
What clinical test might be used to determine whether a patient suffers from cold urticaria?
Clinical history. Ice cube test can be used to confirm (place ice cube on forearm for 4 min and observe area of 10 min, symptoms should develop in 2 min)
Stroking the skin with a fingernail or tongue blade causes a wheal and falre reaction where the skin was touched. What is the diagnosis?
Dermatographism
What form of allergy testing must be used in patients with dermatographism?
Radioallergosorbent test (RAST) or ELISA based blood assays
Treatment for dermatographism
Typically treated with 25-50mg of diphenhydramine or hydroxyzine daily. Seond generation antihistamines work for mild symptoms
What immunoglobulin mediates most food allergies?
IgE
Allergy testing to specific allergens can be done via which two broad techniques?
- In vivo (skin testing)
- In vitro (serum testing)
What immunoglobulin is being tested for with in vivo skin testing
Antigen specific IgE
What are the two most common locations for performing skin testing
- Volar surface of forearm
- Back
What type of in vivo allergy test is performed using scratch, prick/puncture, or patch to challenge a patient by introducing allergen into the epidermis only?
Epicutaneous testing
What type of in vivo allergy test is performed using intradermal techniques to place antifen into the superficial dermis?
Percutaneous testing
What variables impact both epicutaneous and percutaneous skin testing?
- Age of skin (very young and very old may be less sensitive)
- Area of body being tested (sensitivity: upper back> lower back> upper arm> lower arm)
- Skin pigmentation (darker skin colors may be less sensitive)
- Concurrent medications
- Potency and biologic stability of the allergen test extract
- Dermatopathology: dermatographism, eczema -> contraindications, including degree of sensitization, recent anaphylaxis, recent exposure, prior immunotherapy
During skin testing what controls are commonly used?
- Negative control: glycerin-saline, saline, allergen diluent
- Positive control: histamine (10mg/ml)
During skin testing what term is used to describe the white (blanched) raised area at the site of the allergen application? And the area of erythema that extends beyond this raised region?
- Wheal
- Flare
Why is scratch testing (small superficial lacerations ade in the skin, a drop of concentrated antigen then applied) not recommended for skin testing?
Poor reproducibility, variable sensitivity, poor specificity, frequent false positives, painful and reaction may be due to trauma to skin instead of reaction to allergen
What instruments can be used for perform a skin prik or puncture test?
hypodermic needle, solid bore needle, lancet
Passes through the antifen droplet then the skin at a 45-60 degree angle to the skin, lift and break the skin without causing bleeding for the prick test; or the skin device can be passed through the drop at 90 degree angle to the skin for puncture test
After performing a skin prick or puncture how long should you wait before assessing the response?
15-20min
How can you assess the allergic response to a skin test (epicutaneous or percutaneous)
- Longest diameter or longest diameter and orthogonal diameter (perpendicular) of wheel in millimeters
- Presence or absence of flare and size in millimeters
- Presence or abscense of pseudopods
- Classically based on 0-4+ system based on wheal and flare compared with the negative control and presence of absence of pseudopods
Major disadvantages of skin prick tests
Semiqualitative (less objective than intradermal testing). Low degrees of sensitivity may be missed -> false negative results
When should you use an intradermal/percutaneous allergy test?
When the primary goal of testing is increased sensitivity or for evaluating drug or venom anaphylactic reactions
What is the major risk in using intradermal allergy testing and how can this risk be decreased?
Significant systemic reaction (anaphylaxis). Patients should be screened with prick/puncture testing initially. They can also be screened with very dilue concentrations administered intradermally
What part of the body is commonly used for intradermal testing and why?
Volar surface of the forearm. To allow a tourniquet to be placed in case of systemic symptoms
Specificity and sensitivity of single dilution intradermal skin testing compared to skin prick testing.
Intradermal testing has a high sensitivity and less specificity. It has a higher false positive rate than skin prick testing.
What size needle/syringe is recommended during intradermal dilutional testing?
0.5-1.0ml syringe with a 26-30 gauge needle
What volume of antigen concentrate should be injected during intradermal dilutional testing?
0.01mL (goal is to create a 4mm round wheal)
After injection of 0.01ml and creation of a 4mm wheal you appropriately wait 10 minutes to measure the final wheal. If the injected solution was inert dilutent what diameter do you expect based on passive physical diffusion in the skin?
5mm
What is required for a whealing reponse to be considered positive during intradermal dilutional testing?
A final wheal size of 7mm, which is 2mm larger than the expected size at 10 min from physical diffusion alone. Flare is not measured during this type of testing.
During intradermal dilutional testing you note that the no 6 dilution produces a 5mm wheal after 10 min. You then inject the no 5 dilution and again note a 5mm wheal after 10 min. You therefore inject the no 4 dilution and note a 7mm wheal. What should you do?
Then no 4 dilution demonstrated progressive whealing so you must perform a confirmatory wheal by injecting the no 3 dilution. If this is >7mm it would suggest progressive whealing and then no 4 dilution would be considered the end point of the examination. A confirmatory wheal must grow by at least 2mm.
Describe the technique used for intradermal dilutional testing
- Dilutions created and labeled 1-6 with 6 being the weakest concentration and least likely to induce a response
- Inject a negative control 4mm wheal -> 5mm wheal
- Inject a positive control (histamine) 4 mm wheal -> 7mm +
- 0.01ml of no 6 dilution is injected intradermally to create a 4mm wheal
- wait 10 min
- If wheal is 5mm it is considered negative. If 7mm or larger it is considered positive. Continue with dilution no 5
- If at any dilution you note growth of the weal > 2mm over the negative wheal (so 7mm+) continue with the next dilution
- If the next dilution demonstrates progressive growth (an additional 2mm) stop the test. The first wheal to demonstrate growth is the endpoint dilution and the second dilution to demonstrate progressive whealing is the confirmatory wheal
After a positive fivefold sequential intradermal dilutional testing what dilution should be used as a safe starting point for immunotherapy?
The endpoint dilution (the wheal that initiated progression whealing)
What medications can suppress the wheal and flare response for 48-72 hours?
First generation antihistamines
Which medication should be avoided for 7 days because of suppression of the wheal and flair response?
Second generation antihistamines and tricyclic antidepressants, topical glucocorticoids like clobetasol
What are the second generation antihistamines that should be avoided 7 days before skin testing?
Cetirizine, loratidine, fexofenadine, levocetirizine, -> can blunt skin testing for 24-36 hours
Do leukotriene receptor antagonists (e.g. Singulair) need to be stopped before skin testing?
No they have not been shown to routinely inhibit wheal and flare response
What impact do intranasal or systemic corticosteroids have on wheal and flare response during skin testing?
Little to none
To resuscitate a patient adequately in the unlikely event he develops anaphylaxis after skin testing in office what medications should be stopped
Beta blockers
What test measures serum concentrations of allergen specific IgE antibodies?
RAST and modified RAST (has better sensitivity)
Describe steps involved in original RAST immunoassay
- Allergen bound paper disk is placed in test tube
- Patient’s serum is added and antigen specific IgE binds the antigen
- Excess serum and IgE are washed away
- Radiolabeled anti IgE antibodies are added to the test tube and bind the antigen specific IgE already bound to antigen on the paper disk
- Excess is washed away
- Gamma counter is used to determine the amount of bound IgE
Benefits of immunoassay testing over skin testing
Condition of skin doesn’t matter, results aren’t affected by drugs, no risk of anaphylaxis, greater patient convenience, allows for quantitative assessment, greater specificity. May be less sensitive and is more expensive.
Benefits of skin testing over immunoassay
More sensitive, cheaper, faster results, wider variety of antigens to test
What level of total IgE in a patient’s serum is suggestive of allergy?
Greater than 200 IU however lower concentrations don’t rule out allergy
What are the three main strategies used to manage allergy?
- Environmental modification
- Pharmacotherapy
- Immunotherapy
What drug class works on H1 receptors as antagonists, is more effective in treating early phase allergic response related symptoms and can cause sedation as a major side effect?
Antihistamines
Why do first generation antihistamines result in sedation, psychomotor impairment and central nervous system suppresion?
They are highly lipophilic and cross the blood brain barrier
In addition to sedation what two side effects should be considered when prescribing first generation antihistamines?
- Anticholinergic side effects (urinary retention, dry mucous membranes, constipation ect.)
- Tachyphylaxis
Examples of first generation antihistamines
- Diphenhydramine
- Chlorpheniramine
- Azatadine
- Hydroxyzine
- Tiprolidine
- Brompheniramine
- Clemastine (Tavist)
Second generation antihistamines
- Desloratidine (Clarinex)
- Loratidine (Claritin)
- Fexofenadine (Allegra)
- Cetirizine (Zyrtec)
- Levocetirizine (Xyzal)
Name two second generation topical antihistamines that have relatively rapid onset and effectiveness in treating congestion
- Azelastine
- Olopatadine
What drug class works primarily as an alpha1 receptor agonist resulting in vasoconstriction?
Decongestants
What are the primary side effects associated with systemic decongestants such as phenylephrine and pseudoephedrine
- Alpha adrenergic side effects: hypertension, increased appetite, tachycardia, arrhythmia
- Tachyphylaxis (rebound rhinits)
Name four medications that function as topical decongestants
- Tetrahydrozoline
- Naphazoline
- Oxymetazoline
- Phenylephrine
What condition can occur as a result of tachyphylaxis associated with topical decongestants when used for more than three days?
Rhinitis medicamentosa
What is the only topical corticosteroid nasal spray that is pregnancy class B?
Budesonide (Rhinocort)
Name common intranasal topical corticosteroids
- Budesonide (Rhinocort)
- Triamcinolone (Nasocort)
- Fluticasone (Flonase)
- Mometasone (Nasonex)
- Ciclesonide (Omnaris)
- Flunisolide (Nasarel)
Which intranasal corticosteroids are approved for patients as young as 2 years of age
Mometasone (Nasonex) and Fluticasone (flonase)
What intranasal topical medication can be used prophylactically to stabilize mas cell degranulation, is well tolerated due to low systemic absorption (lipophilic) but must be redosed multiple times per day
Cromolyn sodium
Name the leukotriene receptor antagonist that is approved for allergic rhinitis and can be used in children as young as 6 months
Monteleukast (Singulair)
For a patient to be considered for immunotherapy what conditions must be met?
The allergen must cause clinically significant symptoms, and allergen specific IgE must be demonstrated through in vivo or in vitro testing. Environmental avoidance and medical management should be optimized
Contraindications for immunotherapy
- Non IgE mediated symptoms
- Symptoms controlled with maximal medical treatment and environment avoidance
- Atopic dermatitis
- Food allergy
- Allergies related to very short seasonal allergen exposure
- Poorly controlled asthma
- Use of beta blockers
Describe major impact immunotherapy has on the immune system resulting in allergic tolerance and decreased associated symptoms over time
- Increase in number of Th2 and Treg cells
- Increase in IL10 and IL12
- Decrease in IL4 and IL5
- Decreased release of early and late phase inflammatory mediators
- Decreased migration of inflammatory cells
- Suppression of antigen specific IgE over time following initial rise
- Increased levels of IgG4 (blocking antibody vs T helper regulatory cells)
Length of time normally required for immunotherapy to achieve good effect?
3-5 years
What technique is used to administer gradually increasing concentrations of allergy provoking antigen over time to the patient in an effort to modulate allergen specific immune reactions and symptoms via subcutaneous injection?
Subcutaneous immunotherapy (SCIT)
When choosing a starting dose of SCIT what two goals should be achieved?
- Strong enough concentration to induce rapidly an antigen specific response
- Not strong enough to induce a significant local or systemic reaction
Maintenance dose
A dose that is considered the maximum dose that can be delivered without inducing significant local or systemic effects. Delivers a goal cumulative amount of antigen over 3-5 years. Should control symptoms for 1 week
What form of immunotherapy relies on fixed or escalating dose schedules for antigen administered sublingually or orally with the goal of decreasing allergic symptoms, modulating the immune system and providing a safe and easy method for immunotherapy?
Sublingual immunotherapy (SLIT). Used in Europe. Currently off label in the US
- SLIT has predominantly been used for single antigen therapy
What are the two major types of immunity?
- Innate (nonspecific): first line of defense; antigen independent, immediate maximal response, no immunologic memory
- Adaptive (specific immunity): Antigen dependent, delayed maximal response, immunologic memory, lymphocytes and lymphocyte derived immunity
What are the three major components of innate immunity?
- Anatomical boundaries: Epithelium; mechanical movement and trapping from cilia, tears, saliva and mucus; competition from normal flora
- Humoral barrier: Cytokine system, complement system, coagulation; fatty acids, lysozyme, lactoferrin, transferrin, phospholipase, defensins, surfactants, IL-1, TNFalpha, interferons
- Cellular barrier: polymorphonuclear cells, macrophages, NK cells, and eosinophils
In what type of immunity do toll like receptors coordinate the responses of cytokine-complement phagocytic responses?
Innate (nonspecific) immunity
How do NK cells differ from NK T cells
They are part of the innate immune system but can participate in the adaptive immune response. They arise from the lymphoid progenitor cell, which gives rise to T and B cells, do not have a common T cell specific markers (CD3, TCR, MHC ect) they express CD-16, CD-56 and often CD8. They can be activated by IFN to target virally infected or tumor formation within 3 days based on the absence of “self” markers.
The anti tumor effect of NK cells is thought to be due to their unique ability to recognize what?
The absence of self. Although T cells and many other immune effector cells are programmed to recognize nonself proteins produced by viruses or bacteria, NK cells have the ability to recognize when self peptides and proteins have been downregulated as a result of tumor transformation or what might be seen with viral infections. The most commonly encountered down regulated self molecule that might be “recognized” by NK cells are MHC molecules
What is the region of the antigen that is recognized by antigen specific receptors (T and B cells) and immunoglobulins within the adaptive immune system called?
Epitope (determinant)
Tolerance
Defines the ability of a host to ignore self and demonstrate immunologic unresponsiveness to self for both innate and adaptive immune responses
Two subtypes of adaptive immunity
- Humoral immunity -> B cell, antibodies
- Cell mediated -> T cells, cytokines
Three basic steps of adaptive immunity
- Recognition of antigen
- Lymphocyte activation -> production of cytokines, cytokine receptors, and other proteins; clonal expansion of lymphocytes; cellular differentiation (B cell into plasma cell)
- Removal of the offending antigen (clearance)
Primary lymphoid organs
- Thymus
- Bone marrow
Secondary lymphoid organs
- Spleen and lymph nodes
- Mucosal immune system (tonsils, Peyer patches, intraepithelial lymphocytes, lamina propria of mucosal tissues)
- Cutaneous immune system
Langerhans cells
Immature dendritic cell found in the skin and mucosa that contains Birbeck granules, is most prominent in the stratum spinosum of the skin, and is involved in antigen processing
M (microfold) cells
Specialized mucosal immune cell that is responsible for transocytosis (pincytosis) of antigens across the follicular epithelium to germinal centers with Peyer patches within tonsillar tissue
CD (cluster differentiation) markers
Specialized molecules on lymphocyte surfaces that can help other cells (and researchers/clinicians) recognize their level of maturity, lineage and extent of immune activation?
Name the cell associated with the following CD markers:
- CD2
- CD3
- CD4
- CD8
- CD25
- All T cells
- All T cells
- Th1 or Th2 cells
- T suppressor cells (cytotoxic T cells)
- +CD4= Th17 or T regulatory cells
What cell is required to undergo maturation in the thymus and what are the possible outcomes of differentiation?
T cell differentiate in the thymus via both positive and negative differentiation:
- Apoptosis
- CD4 + helper T cell
- CD8+ precytotoxic T cell
What % of CD4+ and CD8+ T cells survive selection in the thymus?
Less than 5%; most say 2% or less
Where does negative selection of developing T cells occur?
Thymic medulla
The process by which developing T cells that react too strongly with self peptides are deleted is called what?
Negative selection
What is the process called by which developing T cells that react appropriately with self peptides are signaled to survive and continue to develop?
Positve selection
TH1 cells
- Develop from naïve CD4 cells (TH0) by intracellular pathogens and Il12
- Inhibits B cells
- Produces IFN gamma (which results in macrophage activation and increased expression of MHC) and IL2 (which promotes proliferation of B and T cells)
- Stimulates cell mediated immunity (activates cytotoxic CD8 cells)
TH2 cells
- Develop from naive CD4 cells by allergens and IL4
- Recruits/activates eosinophils
- Activates B cells
- Produces IL4, IL5, and IL13
- Involved in both allergic disease and humoral immunity
How does the immunologic T cell response to oral antigens differ compared with more systemic responses?
Oral antigens are more likely to induce T cell anergy or T cell tolerance than T cell activation
Two types of MHC molecules
- MHC Class I: display self and non-self antigens, membrane associated glycoprotein, on all nucleated cells
- MHC Class II: display extracellular proteins that are phagocytosed and processed intracellularly before presentation, on antigen presenting cells (dendritic cells, macrophages and B cells)
What type of MHC molecules are expressed by almost all nucleated cells and when downregulated can result in targeted destruction by NK cells and present endogenous antigen
MHC class I
What type of MCH molecules are expressed primarily on antigen presenting cells and lymphocytes (B cells, macrophages, endothelial cells, or dendritic cells primarily) and present processed exogenous antigen
MHC class II
What type of T cell recognizes antigen presented by MHC class II molecules?
Th cells (CD4+)
What type of T cell recognizes antigen presented by MHC class I molecules and kills cells presenting that antigen?
Cytotoxic T cells (CD8+)
What are the components of MHC molecules?
- Extracellular peptide binding region
- Pair of Ig like domains (bind CD4 and CD8)
- Transmembrane region
- Cytoplasmic tail
To activate Th cells, antigen presenting cells must present antigen via an MHC class II molecule as well as secrete which important cell signal?
IL-1
Which cells secrete antibodies and how are they activated?
B cells phagocytose antigen and present it to Th cells via MHC class II molecules. T cell then stimulates the B cell via IL2 and IL4 to mature into an Ig producing plasma cell. Alternatively large antigens can crosslink enough B cell receptors to lead to direct activation of the cells and antibody production
What cell type can be identified by the CD markers 19 and 21
B cells
Why glycoprotein molecules are produced by plasma cells in response to humoral immune stimulation?
Immunoglobulins
What are the basic functions of immunoglobulins?
- Antigen binding
- Effector functions: Complement fixation, neutralization of antibody-dependent cellular cytotoxicity via opsonization (“tagging” an antigen for ingestion and destruction by a phagocyte), stimulation of phagocytosis
What is the basic structure of an immunoglobulin
Four chains (two heavy, two light), variable regions (bind antigen), constant regions, and hinge regions
What component of an immunoglobulin molecule is responsible for most of the effector functions of an antibody
Fc domain
What component of an immunoglobulin molecule is responsible for the specificity of antibodies?
Variable region
Cleavage at the hinge region of an immunoglobulin results in production of what three fragments?
- 1-2. Fab fragments: two identical fragments that contain the light chain and the variable and first constant domain of the heavy chain; binds antigen
- Fc fragments: one fragment containing the remaining heavy chains and their constant regions; may stimulate complement
Five classes of immunoglobulins
- Vary based on the amino acid sequences in the constant region of the heavy chain
- IgA (serum, monomer; secretions, dimer): found in external secretions, primary defense against local mucosal infections, neutralizes foreign substances
- IgD (monomer): antigen receptor on B cells
- IgE (monomer): binds mast cells and is involved in alelrgic and parasitic infections
- IgG (monomer): recall immune response and can cross placenta
- IgM (pentamer): antigen receptor of B cells
IgA
Makes up more than 70% of the total body immunoglobulin (only 15% of serum immunoglobulin). Found in mucosal secretions and is important in preventing microorganisms from invading the body
How do IgA molecules primarily mediate mucosal immunity?
They are weak activators of complement and mediate their affects primarily via neutralization of antigen and prevention of systemic access
Two subclasses of IgA
- IgA1 (~85% serum): strong immune response to protein antigens. Some response to polysaccharide and lipopolysaccharides
- IgA2(~15% serum): key player in defense against mucosal invasion via immune response to polysaccharide and lipopolysaccharide antigens
What immunoglobulin deficiency is largely asymptomatic correlating with the poorly understood function of its associated monomeric glycoprotein?
IgD
What is the structure of IgM?
- Pentamer made up of five immunoglobulin subunits linked by a J chain
What immunoglobulin is produced first in a humoral immune response and is excellent at binding completment
IgM
What conditions can lead to high levels of IgE antibodies?
Allergic disease, lymphoma, IgE myeloma, systemic parasitosis, TB, HIV, Churg Strauss
IgG
- Most prevalent in serum and extravascular spaces
- Only immunoglobulin to cross the placenta
- Plays important role in immunologic memory)
- Functions to fix complement and activate macrophages, monocytes, PMNs and some lymphocytes via opsonization
Describe the function of the four IgG subclasses
- IgG1 (60-70%): response to protein and viral antigens, classic complement cascade activation, opsonization
- IgG2 (20-30%): response to bacterial and polysaccharide antigens (i.e pneumococcus), opsonization, complement activation
- IgG3 (5-8%): response to protein and viral antigens, opsonization, complement activation
- IgG4 (1-4%): minimal opsonization, no complement activation, may be involved in immune response to parasites
What nonantibody proteins act as mediators between cells, result in signaling cascades and can be produced both by immune (innate and cell mediated) and nonimmune system cells?
Cytokines
INF
cytokine that results in an antiviral response
Lymphokine
cytokine that is produced by lymphocytes
Interluekin
Cytokine produced by leukocytes and effect the function of other leukocytes
TNF alpha
Cytokine that results in an acute inflammatory response to gram negative bacteria. Secreted by monocytes, macrophages, T, B and NK cells
Colony stimulating factor
Cytokine that influences maturation and release of bone marrow cell populations
IL2
Produced by Th cells, major growth factor for T cells, B cells and NK cells
IL3
Stimulates bone marrow immune cells to expand, especially mast cells and eosinophils
IL4
produced by macrophages, mast cells and T cells. Stimulates development of Th cells, stimulates B cell immunoglobulin class switch to IgE
IL5
Produced by Th cells, promotes maturation of B cells and eosinophils
Transforming growth factor (TGF) beta
Produced by T cells, among others, and inhibits proliferation of T cells and macrophages and inhibits the effect of proinflammatory cytokines on polymorphonuclear cells and endothelial cells
IL10
Functions to regulate both innate and adaptive immune system by inhibiting macrophages, cytokine synthesis, and antigen presenting cells and is produced by macrophages and CD4+ T cells
TNF alpha
- Produced by activated macrophages (response to lipopolysaccharide of gram negative bacteria)
- Mediates acute inflammation, stimulates thalamus to produce a fever
IL1
- Produced by activated macrophages, mediates acute inflammation, stimulates T cells
Type I interferons (INF alpha and beta)
- Produced by many different cells to inhibit viral replication, increase MHC class I expression in cells making them more susceptible to cytotoxic T cells, activate NK cells
INF gamma
Produced by TH1 cells, produces a myriad of direct cytotoxic effects
What is the clinical impact of IgG1 deficiency?
Generalized hypogammaglobulinemia. Often associated with IgG3 deficiency
When patients have significant IgG1 deficiency in combination with IgA and or IgM deficiency what is the diagnosis
Common variable immunodeficiency
Selective IgG1 deficiencies can result in frequent and or repeated infections of what two organs?
Upper (sinuses) and lower respiratory tracts
IgG2 deficiency
- Important in the defense against polysaccharide capsular antigens
- Most susceptible to strep pneumo, haemophilus influenza type B, neisseria meningitidis
- Most common in children
- Should receive conjugated vaccines
IgG3 deficiency
- Can result in increased susceptibility to viral infections as well as Moraxella catarrhalis and streptococcus pyogenes resulting in recurrent sinopulmonary and GI infections as well as recurrent lymphocytic meningitis
- IgG1 is often deficient as well
- Most common deficiency in adults
IgA deficiency
Patients often asymptomatic. One of the most common immunodeficiencies. May have recurrent sinopulmonary or GI infections, skin infections, anaphylaxis with transfusions or autoimmune disorders.
Wiskott Aldrich Syndrome
- X linked
- Can present with eczema, thrombocytopenia, recurrent otitis media, pneumonia and sinusitis
- Elevated levels of IgE and IgA but decreased levels of IgM
Bruton agammaglobulinemia
- X linked
- Defect in tyrosine kinase resulting in inability of B cells to mature
- Can result in severe and recurrent otits media, sinopulmonary infections, pneumonia, autoimmune disorders
- Start to show symptoms after 6 months of age after mother’s antibodies have worn off
- Will have low levels of all immunoglobulin types
Patients with Bruton agammaglobulinemia develop nasses in what organ?
Thymus
Patients with X linked agammaglobulinemia have recurrent infections secondary to a low level of which antibody isotypes?
All antibody isotypes
What form of immune responses are impaired in DeGeorge syndrome?
T cell mediated immune responses are impaired or absent secondary to thymic agenesis
What are the diagnostic criteria for AIDS?
An AIDS defining illness (e.g. Kaposi sarcoma) or a CD4+ T cell count less than 200 cells or a CD4% less than 14%
Chronic granulomatous disease
- Commonly X linked
- Results in inability of phagocytes to kill catalse positive organisms as a result of dysfunction of intracellular hydrogen peroxide production via the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex
Receptors of innate immune system
- Pattern recognition receptors
- Toll like receptors
T cell types
- T helper 2 (TH2): specialize in facilitating B cell antibody response
- T helper 1 (TH1): specialize in macrophage activation
- T helper 17 (TH17): involved in autoimmunity
- Regulatory T cells: involved in autoimmunity
Mast cell degranulation
Results in vasodilation, increase capillary permeability, bronchoconstriction, tissue edema
Examples of type II hypersensitivity reactions
- Hemolytic anemia
- Transfusion reaction
- Acute graft versus host disease
- Goodpasture syndrome
- Myasthenia gravis
Examples of type III hypersensitivity reactions
- Serum sickness
- Poststreptococcal glomerulonephritis
- Angioedema
- Gastrointestinal intolerance
Examples of type IV hypersensitivity reactions
- Dermatitis
- TB
- Sarcoidosis
- Candidiasis
Allergic rhinitis common allergens in infants/children
- milk
- eggs
- soy
- wheat
- dust mites
- pet dander
Allergic rhinitis common allergens in adolescents/adults
- pollens
- animal dander
- insects
- molds
- foods
C1 esterase deficiency
Deficiency in the complement pathway and cause of hereditary angioedema
Lymph node anatomy
- Blood vessels come and go through the hilus
- Outside is the cortex surrounding a paracortex surrounding the medulla
- Cortex contains primary and secondary lymphoid follicles in which B cells predominant
- Paracortex contains T cells
- Medulla contains B cells, T cells and APCs
