Week 6 Flashcards
Type I Immunopathology
Allergic Hypersensitivity
IgE, Mast cells, eosinophil mediated
Role of IgG in Helminth infestation
Worm infestation → both IgE and IgG
IgG binds worm or its ova and activates complement → C3a, C5a attract neutrophils → BUT neutrophils lack helminthocidal mechanism…sad
Role of IgE, mast cells, and eosinophils in Helminth infestation
Worms shed antigens that mast cells bind on IgE receptors (cross link two IgE receptors)→ histamine secretion and later prostaglandin and leukotriene secretion
→ attract eosinophils in large numbers → kill helminth with Major Basic Protein (MBP) which is highly toxic to helminths
M2 macrophages in Helminth infestation
Th2 cells go out into body, find helminth antigens presented by APCs → attract BOTH eosinophils and M2 Macrophages (Th2 IL-4, IL-5, and IL-13 → M2)
M2 macrophages heal damage and wall off M1-resistant invaders
Eosinophilia indicative of parasitic disease or severe Type I immunopathology
General steps of Type I immunopathology: 4 steps
1) IgE binds strongly to FcER1 receptors on mast cells
2) 2 adjacent IgE molecules bound by mast cells and are cross-linked by allergen
3) → mast cell releases granules (histamine)
4) Histamine → local/systemic vasodilation, increased permeability, gut/bronchial smooth muscle contraction
Allergen
something that triggers an allergy, the “antigen”, plants/flowers, dust, animal dander, tobacco smoke
Anaphylaxis
severe, life-threatening Type I hypersensitivity reaction
Incidence of Atopic Disease
15% of general pop experience allergic symptoms at some time in their lives
35% in newborns with one allergic parent
65% in newborns with two allergic parents
Allergic seasonal rhinitis is the most common, food allergy, eczema in children and asthma.
Incidence of asthma nearly doubled from 1980 to 1995 (and the increase is REAL, not just better diagnostics).
Hypersensitivity Immediate Reaction (4 steps)
1) IgE binds to basophils or mast cells on IgE receptor (FcERI)
2) Reaction with allergens: IgE-loaded mast cells release contents of granules when two adjacent IgE molecules are cross-linked by allergen
3) Mediator release: histamine, heparin, enzymes, TNF pre-formed and released quickly from mast cells and basophils
4) Effects of mediators on target tissues and cells
Histamine → itch, blood vessel dilation, leakiness
½ life is 1 minute (transient reaction)
In order to activate mast cell release of granules, there must be …
Need 2 adjacent IgEs bound on mast cell specific for 2 epitopes on same allergenic protein
Pasma IgE and allergies
Plasma IgE usually very low because it binds so strongly to IgE receptor
Allergic people may have higher serum IgE
_______ can treat immediate hypersensitivity reaction but CANNOT treat late phase reaction
antihistamines
Late phase hypersensitivity reaction begins _________
4-10 hours post immediate reaction
Late phase hypersensitivity involves release of _______ and _______ which act as ________
Prostaglandins and leukotrienes
Eosinophil Chemotactic Factor of Anaphylaxis
______ and _____ attract eosinophils to a late phase hypersensitivity reaction
IL-4 (secreted by Th2) and ECF-A (PGE + LT)
Atopic Disease
characterized by abnormal IgE response to environmental antigen (mediated by Th2 cells)
_______ are common in atopic disease
cross reactions
Atopic State
prone to develop any range of allergic syndromes
Examples of Atopic Disease (4)
1) Allergic (Seasonal) Rhinitis (aka hay fever)
2) Eczema (atopic dermatitis)
3) Oral allergy Syndrome (OAS)
4) Asthma
Oral Allergy syndrome (OAS)
food allergy that occurs immediately when offending food put in mouth (antigens immediately passed to mast cells)
Tingling lips and tongue, itching, swelling of lips
Hyper IgE Syndrome
Inability to make IFN-y effectively → poor Th1 responses, Th2 predominates
High serum IgE, skin abscesses, fungal or pseudomonas pneumonia
Asthma
reversible bronchoconstriction disease with progressive inflammation leading to fibrosis
Test for asthma with _______
spirometry (measures airflow)
Spirometry
measures air flow
FEV1 = volume of air forcibly exhaled from full lungs in 1 second)
Measure at baseline, and after bronchodilator
Significant improvement after bronchodilation → bronchoconstrictive disease.
Inhaled Glucocorticoids in Asthma Treatment
Low absorption (avoid systemic side effects)
GCs inhibit production of arachidonic acid from phospholipids and block both PG and LT synthesis
Used to treat asthma early to prevent the late-phase reactants and Th2 cells present in the lung that are pro-inflammatory
Intradermal skin test
Drop of allergen extract placed on forearm, needle used to prick epidermis under drop
Results observed at 15 to 20 minutes and wheal/diameter of central raised area is measured (5/15 mm).
Must test with buffer to control for skin hyperreactivity.
Drawbacks of intradermal skin test
1) Patients observed for 20-30 minutes after test to make sure no problems result
2) Positive skin test does not necessarily mean symptoms are due to the allergen
- Levels of sensitivity may be sub-clinical even with positive test
- Symptoms might come from cross-reaction with test extract
ImmunoCAP-FEIA
Allergen fixed to a capsule, add patient’s serum, wash away unbound proteins
Presence of bound IgE quantified with enzyme-tagged antibodies (becomes fluorescent)
Score above a certain level correlates with symptoms
COMPLETELY SAFE (unlike skin test)
Arthus Reaction
- local manifestation of immune complex disease (Type III)
- Seen with booster shots
- Pt has pre-existing ab to immunogen so when antigen deposited by injection, –> IgG based immune complexes form locally in dermal blood vessels. → activate complement and neutrophils
- Symptoms after 4-6 hours, last 1 day
- This is why your arm is SORE after shots!
Local innocent bystander effect in arthus reaction
IgG based immune complexes in dermal blood vessels.
dermal blood vessels are normal tissues that are damaged because of immune complexes formed by the booster antigen+pre-existing antibodies
Systemic innocent bystander effect in serum sickness
damage to normal tissue in the body wherever the serum sickness immune complexes deposit.
One-Shot Serum Sickness - 4 steps
1) Injection of animal serum → antigen excess with minimal complex formation
2) Begin to make ab against foreign protein → complex formation in antigen excess
3) Makes complexes just the right size to get lodged in BM
4) Causes symptoms until enough ab made to form large complexes that can be cleared by RES
Gradually, equivalence between ab and antigen in circulation → large complexes form → symptoms resolve
Symptoms for serum sickness begin ________ and last ________ (until…)
begin 10-14 days after injection of animal serum
last 7 days
until enough ab made to form large complexes that can be cleared by RE system
How to avoid serum sickness?
affinity purification can lower dose of foreign protein by chopping off and discarding Fc part (only use Fab and Fab2)
Tissues typically damaged with immune complex deposition
Complexes trapped in capillary beds where there is the most filtration of blood
-Joints, pleura, peritoneum, skin, choroid plexus, kidney
All immune complex conditions have _______ constellation of symptoms.
Nature of ______ is irrelevant
similar
antigen
Requirement for exogenous antigens to cause type III reaction (3)
1) Antigen given in large quantity (so antigen still present when ab made)
2) Antigen may be in a depot (so it persists)
3) Antigen is self-replicating (so it persists)
Polyarteritis nodosa
antibody/hepatitis B or C viral protein immune complexes get stuck in basement membranes of medium sized arteries.
Urticaria (hive) formation in type III reaction
Release of histamine (mast cells) after immune complexes activate complement → increased inflammation and urticaria (hives).
Hives caused by leakage of capillaries into dermis → edema, distinctive red rash.
Rheumatoid Arthritis and Type III immunopatholgy
Endogenous antigen, Rheumatoid Factor (IgM antibody to IgG)
Type III manifestation of disease with Type II / Type IV components also
RF levels correlate with disease activity sort of - useful in diagnosis of RA
IGA Nephropathy and Type III immunopathology
Most common form of primary glomerulonephritis in the world.
Co-deposition of IgA and IgG in renal glomerulus.
IgA and IgG antibodies bind under-glycosylated IgA1 in kidney and form complexes that get trapped in renal glomerulus.
Systemic Lupus Erythematosus (SLE) as a type III immunopatholgoy
Endogenous antigen = IgG antibody to ds-DNA and histones
dsDNA complexes deposit preferentially in kidney leading to glomerulonephritis
Characteristic butterfly rash post-UV exposure because DNA-releasing cells
Diagnosis of Type III immunopathology with…
1) Total hemolytic Complement (CH50) → often decreased in serum
2) Immune complexes may be detectable in blood → Cryoglobulins
3) Rheumatoid Factor
4) Renal Biopsy
Cryoglobulins
fluffy white precipitate formed after 24hrs in fridge
Immune complexes less soluble in cold
They are “Mixed” cryoglobulins (antigen + Ab)
Indicates pt at risk for developing immune complexes, may need to receive anti-inflammatory or immunosuppressive treatment
Rheumatoid Factor
IgM antibody against patient’s own IgG.
NOT primary mechanisms of pathogenesis, but its presence is useful in diagnosing Rheumatoid arthritis
Post-streptococcal glomerulonephritis
10-14 days after inadequately treated strep infection → glomerulonephritis due to strep antigen/ab immune complexes getting stuck in kidney BM and activating complement
Signs and symptoms of post-strep glomerulonephritis
nausea, vomiting, fever, malaise, HTN, reduced urine output, hematuria, joint pain.
- Serum complement levels are ↓
- renal biopsy “lumpy bumpy”
post-strep glomerulonephritis typically seen in…
developing countries when antibiotics are delayed or unavailable.
Renal biopsy in diagnosis of post-strep glomerulonephritis
Place sections of kidney with glomerulus on slide overlaid with fluorescent labeled goat Ab to human Ig
“lumpy bumpy” pattern on BM → antigen-antibody complexes present
If a clearly defined pattern along BM → Goodpasture’s syndrome
Hypersensitivity pneumonitis - “farmer’s lung”
caused by chronic exposure to Actinomycetes (bacteria in moldy hay)
Chronic exposure → develop serum IgG abs to bacteria
One day farmer inhales enough antigen (diffuses through alveoli into capillaries) → antigen-antibody complexes form in lungs
Complement and neutrophils cause symptoms
Called “allergic” but is Type III, NOT Type I
Symptoms of hypersensitivity pneumonitis
Acute attack: 4-8 hours after exposure with SOB, dry cough, fever, malaise, tachycardia.
Most episodes are more chronic with same symptoms + arthritis.
