Hunter-Types III & IV Hypersensitivity Flashcards
Type III Hypersensitivity reactions are Ig___ mediated.
IgG
What is the nature of the antigen in Type III reactions?
soluble antigen
What is the effector mechanism in Type III rxns?
complement, phagocytes
What is an example of a Type III reaction?
serum sickness, arthrus reaction, systemic lupus erythematosus
What is an immune complex?
antigen-antibody complex
What are the 4 categories of immune complex disease?
Persistent infection
Injected Antigen
Inhaled Antigen
Autoimmunity
What is the antigen for a persistent infection immune complex disease? What are some examples of this?
Antigen: Microbial Antigens (Acute–Subacute)
Examples: Streptococcal Infections, Malaria, Viral hepatitis, and Many Others
What is the antigen for an injected antigen immune complex disease? What are some examples of this?
drugs & biologics (acute)
Arthus Reaction, Serum Sickness
What is the antigen for an inhaled antigen immune complex disease? What are some examples of this?
Antigen: Molds, Spores, Chemicals
(Acute)
Examples: Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)
What is the antigen for autoimmunity immune complex diseases? What are some examples of this?
Antigen: Self Antigens (Chronic Disease)
Examples: Systemic Lupus Erythematosis, Rheumatoid arthritis
If you have a high dose of IV antigen…what are some possible places of resulting disease? Where would the deposits be?
Vasculitis: blood vessel walls
Nephritis: renal glomeruli
Arthritis: joint spaces
If you have a subcutaneous dose of antigen…what are some possible resulting diseases? Where would the deposits be?
Arthrus reaction in the perivascular space
If you have an inhaled antigen…what are some possible resulting diseases? Where would the deposits be?
Farmer’s Lung
Alveolar/Capillary Interface
What type of hypersensitivity reaction is lupus?
TYPE III
Where do the immune complexes embed themselves when they haunt the kidney in the form of nephritis? Why is the kidney so sensitive to immune complexes?
they embed themselves in the basement membrane of the glomeruli
**perfect storm b/c the glomeruli have a small capillary bed, highly vascular, under high pressure
When do you get disease with the presence of immune complexes?
when the amount of immune complexes produced exceeds the body’s ability to get rid of them. maybe they are embedded somewhere or maybe there is a lot of them.
Describe in detail what causes vasculitis. What will this person show if the damage is only somewhat bad? What if it is really bad?
when the immune complexes in the b.v. squeeze b/w the endothelial cells & get stuck in the basement membrane. Get inflammation & blood vessel damage. If it is a little bad: petechiae & if it is really bad you get purpura.
Joint spaces are highly ______ making them vulnerable to immune complex disease, such as arthritis.
vascularized!
What is an arthrus reaction?
this is when you form a bunch of immune complexes right underneath the skin–a kind of vaccine reaction
What are 2 other names for Farmer’s Lung?
hypersensitivity pneumonitis
extrinsic alveolar disease
Describe the time course of the formation of immune complexes.
When you first see a bunch of an antigen you don’t have antibodies for it! So the antigen is in excess
Takes 4-6 days to produce antibodies.
Once they start getting produced you have a few immune complexes, but you are still in antigen excess. B/c they are so small, they don’t fix complement & they can’t be readily cleared. Therefore, they can get deposited in vasculature.
Once you get an equivalent level of antigen & antibody or once you get antibody excess–it can bind complement & be cleared.
When might a cancer patient be in antigen excess during one of their treatments?
Maybe they are treated with monoclonal antibodies. For a bit they may be in antigen excess & have a difficult time clearing their immune complexes.
Describe how immune complexes are normally cleared.
The immune complex is not in antigen excess. it activates the complement. This produces C3b & C4b molecules that attach to the immune complex. C3b & C4b bind CR1 on the RBC. The RBC takes it for a trip to the spleen or the liver. Splenic macrophages or Kupffer cells then bind the immune complex via Fc receptor & release the RBCs to go on their merry way.
When does this normal system of clearing immune complexes break down?
when you have a complement deficiency or an overwhelming infection or massive amounts of complexes or a persistent infection. The immune complexes can’t get out so they embed themselves in small vasculature.
Which areas of vasculature do immune complexes like to deposit?
glomeruli b/c it is a small capillary bed w/ high pressure
small vasculature of the skin or joints
can sometimes get immune complexes stuck in arteries if it is at a point of bifurcation where there is turbulent flow. This turbulence gives the immune complex time to embed itself b/w the endothelial cells onto the basement membrane.
What happens after immune complexes embed themselves in the basement membrane of vasculature?
Complement is activated releasing anaphylatoxins (C5a and C3a)
Neutrophils are recruited to site, bind to immune complexes by their Fc receptors, and become activated
Frustrated phagocytosis results in granule exocytosis and inflammatory mediators and enzymes cause tissue destruction
If you get a bunch of immune complexes embedded in your glomeruli…what will the patient likely experience?
hematuria & proteinuria
**not caused by the microorganism that invaded the pt, but by the attack of the immune complex.
A 14-year-old Hispanic male presents with a 3-day complaint of “cola-colored urine.” He has been your patient since birth and has experienced no major illnesses or injuries, is active in band and cross-country, and denies drug use or sexual activity. Two weeks ago he had 2 days of fever and a sore throat, but he improved spontaneously and has been well since. His review of systems is remarkable only for his slightly puffy eyes, which he attributes to late-night studying for final examinations. On physical examination he is afebrile, his blood pressure is 135/90 mm Hg, he is active and nontoxic in appearance, but he has some periorbital edema. The urine dipstick has a specific gravity of 1.035 and contains 2+ blood and 2+ protein. You centrifuge the urine, resuspend the sediment, and identify red blood cell casts under the microscope.
What does this patient have?
Post-Streptococcal Glomerulonephritis
Post-streptococcal glomerulo-nephritis is the most common post-infectious acute proliferative nephritis and has a good prognosis
What would you see in the glomerulus of a person with Post-streptococcal glomerulo-nephritis as opposed to a healthy kidney?
glomerular hypercellularity due to intracapillary leukocytes & proliferation of intrinsic glomerular cells
What would an immunofluorescent stain of the glomerulus show?
demonstrates discrete, coarsly granular (“lumpy-bumpy”) deposits of complement protein C3 and IgG
What does it take to confirm a diagnosis of Post-streptococcal glomerulo-nephritis?
Confirming the diagnosis requires evidence of invasive Streptococcus pyogenes infection such as a elevated anti-DNAase B titer
**might want to also look for high IgG serum levels
T/F There are certain types of strep that could potentially damage certain organs via hypersensitivity disease.
True. Some forms of strep are more cardiogenic than nephrogenic. Impetigo is a skin strep infection that could also cause similar problems.
Which is a type II sensitivity & which is a type III sensitivity? Post-streptococcal glomerulnephritis
Rheumatic Fever
Rheumatic Fever: Type II
Post-streptococcal Glomerulonephritis: Type III
Both involve IgG
In a person with chronic Hep B who dies of kidney failure…what would biopsy of their glomeruli likely show?
Deposition of a lot of immune complexes. lots of antigen & antibody. FITC-anti-hepatitis B antigen rhodamine anti-IgM **this shows that even viral infections can lead to the formation of immune complexes.
Describe in detail how an arthrus reaction occurs.
Someone goes in for a booster vaccine & has already had a subclinical infection of that same microorganism. Thus, they already have IgG antibodies.
You get a lot of immune complex formation.
Activation of FCgammaRIII on mast cells leads to their degranulation.
Get inflammation.
**will end up looking kind of like a skin test even tho it is just the site of a vaccination.
A healthy 4-year-old female received a booster dose of DTaP vaccine in her right arm. She developed marked right arm swelling, redness and pain within 6 hours of receiving the booster vaccination. Her vital signs were normal except a temperature of 38.5 ˚C. She had received her primary immunization series at 6, 10 and 14 weeks of age, consisting of trivalent oral polio vaccine administered by mouth, hepatitis B virus vaccine, Haemophilus vaccine, and DTaP vaccine. No adverse reactions had been noted following those immunizations. A dose of acetaminophen was given every 4 hours for 24 hours for pain and the child was observed at home. No further interventions were required. Fever defervesced within 12 hours. Limb edema and tenderness resolved gradually over the following two days, and the child resumed increasingly full use of the affected limb as the other clinical signs resolved. Within a week she had made a full recovery.
What happened to this child?
Arthrus reaction. Must have been exposed to this antigen before.
Immune complexes form in the setting of high local concentration of vaccine antigens and high circulating antibody concentrations
A local vasculitis is associated with deposition of immune complexes and complement activation
Reactions are characterized by severe pain, swelling, induration, edema, hemorrhage, and occasionally necrosis
This is a form of local type III hypersensitivity reaction occurring in a previously sensitized person, with signs and symptoms typically occuring 4–12 hours after vaccination
Gregory was brought to the Children’s Hospital Emergency Room with a 2 day history of high fever, cough, and shortness of breath. A chest radiograph revealed an opaque area over the entire lower lobe of the left lung, and a diagnosis of lobar pneumonia was made. Gregory was admitted to the hospital and treated with intravenous penicillin. On his ninth hospital day he had no fever and his chest radiograph had improved. The next morning, Gregory had puffy eyes, and welts resembling large hives on his abdomen. He was given the antihistamine Benadryl (diphenhydramine hydrochloride) orally, and penicillin was discontinued. Two hours later he developed a tight feeling in the throat, a swollen face, and widespread urticaria (hives). The urticarial rash spread over his trunk, back, neck, and face, and in places became confluent. There were also purpuric lesions, caused by hemorrhaging of small blood vessels under the skin, on his feet and around his ankles.
What is his diagnosis? Is this an issue with penicillin that is Type 1, 2, or 3?
Penicillin-Induced Serum Sickness
Type III Hypersensitivity
**you can tell this b/c of the purpura
What are the names for penicillin issues with Type 1, 2, & 3?
Type 1: Anaphylaxis reaction
Type 2: Drug Induced Hemolytic Anemia
Type 3: Penicillin-induced serum sickness
If you don’t know which type of penicillin reaction you are dealing with…what is the treatment?
well, you kind of don’t need to know b/c the treatment is basically the same all around.
stop the penicillin.
maybe given anti-histamine b/c histamine release by mast cells is present in every type of reaction. This release can be triggered by IgE or IgG
Describe in detail what causes the Type III hypersensitivity reaction to penicillin.
The chemically reactive penicilloyl moiety binds to self proteins and induces an antibody response
IgG anti-penicillin antibodies form immune complexes with penicillin
Complement activation releases C3a which causes histamine release from mast cells and urticaria (hives)
Immune complexes deposit in small blood vessels causing vasculitis, arthritis, and nephritis
**this is transient–gone when the antigen is gone
What causes the purpura of the Type III reaction?
significant damage to the blood vessels
If you saw a peak on a graph w/ a slope up & down of antibody-antigen immune complex formation….at which point on that line are you in danger of type III hypersensitivity?
the rising slope b/c that is when the antigen is in excess & the immune complexes can’t activate complement for removal.
What are all of the names for Farmer’s Lung?
extrinsic allergic alveolitis
hypersensitivity pneumonitis
Bird Fancier’s Disease
Describe what happens with Farmer’s Lung.
farmers move hay & inhale a bunch of molds & spores.
They get to the alveoli & penetrate thru the cell lining.
Induce an antibody response–igG
Immune complex formation.
Mast cells are engaged.
Get inflammation w/ release of anaphylatoxins
If it is chronic inflammation you can get fibrosis of the lung–almost like COPD.
What is a test that you can do to see if a pt has Farmer’s Lung?
can test for antibodies that are common & found on the farm
A 36-year-old farmer was admitted as an emergency with headache, fever, shortness of breath, a non-productive cough and myalgia. These symptoms came on suddenly. He had no features of upper respiratory tract infection, although he had had similar symptoms 3 weeks previously and had been treated with antibiotics. On examination, he had a tachycardia of 120/min, a temperature of 38 °C and bilateral widespread crepitations. His chest X-ray showed faint mottling in the middle and lower zones of both lung fields, but no hilar enlargement. He had a high white cell count (15 × 106/ml). A TB test was negative. Lung function studies showed a restrictive defect. His serum contained precipitating antibodies to Micropolyspora faeni and Aspergillus fumigatus. What does this pt likely have?
Which of the pathogens listed is more dangerous?
Farmer’s lung
Aspergillus fumigatus is a serious human pathogen
How can you treat Farmer’s Lung?
shut down the inflammation w/ corticosteroids
avoid hay or whatever is presenting the allergen
if there isn’t fibrosis, the person should recover
if there already is–sorta like COPD from an extrinsic source
What are the different types of immune reactants in Type IV hypersensitivity reactions?
Th1
Th2
Th17
CTL
What type of antigen reacts with Th1 & Th2 as opposed to the nature of the antigen that reacts to CTL?
Th1 & Th2: soluble antigen
CTL: cell-associated antigen
Describe the effector mechanism with Th1 cells in Type IV reactions.
macrophage activation
involves IFNgamma, chemokines, cytokines, cytotoxins
What is an example of a Type IV hypersensitivity reaction that involves Th1 cells as the immune reactants?
allergic contact dermatitis
tuberculin reaction
Describe the effector mechanism with Th2 cells in Type IV reactions.
IgE production, eosinophil activation, mastocytosis
What are some examples of Type IV hypersensitivity reactions that involve Th2 cells as the immune reactants?
chronic asthma, chronic allergic rhinitis
What is the effector mechanism for CTL in Type IV reactions?
it basically involves cytotoxicity
What are some examples of Type IV hypersensitivity reactions that involves CTL as the immune reactants?
graft rejection
allergic contact dermatitis to poison ivy
Type IV hypersensitivity is also called what?
Delayed Type Hypersensitivity
Describe what is involved in Th1 mechanism for Type IV in more detail.
The TH1 delayed-type hypersensitivity (DTH) response is orchestrated by IL-12 produced by macrophages; T cells make IFN-g that further activates macrophages
Describe in more detail what is involved in Th17 mechanism for Type IV in more detail.
The TH17 reaction is driven by IL-23 and TGF-b produced by macrophages; T cells make IL-17 and IL-22 that recruit and activate neutrophils
Describe what is involved in the CD8 delayed type hypersensitivity reaction.
The CD8 DTH response involves cytotoxicity and is a component of several autoimmune diseases like Type I diabetes; CD8 T cells also make IFN-g
Tuberculin Reaction: The Prototype of Delayed-Type Hypersensitivity
Describe it in detail.
The person has already been sensitized to TB.
You inject PPD subcu.
This is internalized by dendritic cells (APCs) & the MHC II w/ the antigen interacts with the CD4 Th1 cells. Th1 release TNFalpha & interferon gamma & chemokines. These bring in a mononuclear cell infiltrate.You get a little bump of inflammation that shows that you have memory cells.
How long does it take for a delayed type hypersensitivity response w/ PPD?
24-72 hours
Why do have all of these Th1 cells chillin’ around in the PPD pt?
b/c they were exposed before. CD4 cells at that time differentiated in the Th1 direction.
If you see granulomas…what types of cells are probably present? If this is in the lung–what do we have?
CD4, giant cells, epitheloid cells
If in the lungs–TB.
Which cells are activated in allergic contact dermatitis?
CD4 most commonly, could also be CD8 cells
What is allergic contact dermatitis?
antigens are highly reactive small molecules that can penetrate the skin.
these chemicals react with self proteins & form hapten-protein complexes.
If the person has the unfortunate HLA to give the right MHC II then the langerhans’ dendritic cell will take it up & present a hapten-peptide.
The APC will go to the lymph node & activate T cells. The memory T cells will migrate to the dermis.
So…a person is sensitized to a small chemical antigen. What happens to the pt upon second exposure?
Dendritic cell gets a hold of the same hapten-protein conjugate.The memory T cells interacts with the dendritic cell & is activated. Mediators, including IFN-gamma, are released by the T cell. This stimulates keratinocytes to release things like cytokines & chemokines that get monocytes in there & get some inflammation going.
If you get a drop of DMSO on the back of your hand…what happens to you?
in a few seconds you taste garlic!! Crazy!!
What does CXC stand for?
chemokines–these are things that attract monocytes.
A 7-year-old boy had enjoyed perfect health until 2 days after he returned from a hike with his summer camp group. Itchy red skin eruptions had appeared all along his right arm. Within a day or two, the rash had spread to his trunk, face, and genitals. He was taken to Children’s Hospital. Physical examination of his trunk and extremities revealed large patches of raised, red, elongated blisters oozing a clear fluid.
What does this patient have?
contact hypersensitivity to poison ivy
What would be the proper treatment for contact hypersensitivity to poison ivy if it was mild? If it progressed to something more serious?
SYSTEMIC CORTICOSTEROIDS
He was given corticosteroid-containing cream to apply to the skin lesions three times a day, and Benadryl (25 mg) to take orally three times a day. He was asked to shampoo his hair, wash his body thoroughly with soap and water, and cut his nails short. Two days later his parents reported that although no new eruptions had appeared, the old lesions were not significantly better. He was then given the corticosteroid prednisone orally, starting at a dose of 2 mg/kg per day and gradually decreased over a period of 2 weeks. Within a week, the rash had almost disappeared.
What is the chemical in the poison ivy that causes problems?
Pentadecacatechol or urushiol
How does contact dermatitis present?
Contact dermatitis presents with epidermal blisters (vesicles) with dermal and epidermal mononuclear infiltrates
Remember: this person has been exposed previously with mild to no symptoms & was sensitized. This is the second exposure.
A 47-year-old woman presented with a 3-week history of an acute rash that started beneath her new watch band. She had previously noted that she could not wear cheap earrings without triggering a rash on her ear lobes. There was no past medical history of note and no personal or family history of atopy. On examination, two patches of dermatitis were seen over the presenting areas.
What does this patient have?
nickel-induced contact dermatitis
**this patient for a definitive diagnosis responded strongly to nickel sulfate
What happens in nickel dermatitis?
chemically reactive metals like nickel bind to host proteins & activate T cells. These cells release IFN gamma. The IFNg activates the keratinocytes. These release chemokines that attract a mononuclear cell infiltrate.
What is the treatment for nickel dermatitis?
only avoidance of contact with nickel. Pick a different watch!
What are 2 common sensitivities that people in the medical field come into contact with? Things that can cause contact dermatitis…
acrylate
latex
