Immunopathology - SRS,LM and whoever else wants a piece I reckon, this one is big. Flashcards
What cells mediate Type I reactions?
TH2 cells, by cytokines
What causes B cells to class switch to IgE?
IL-4
Type II hypersensitivity reactions are mediated by?
Antibodies - IgG and IgM, cause injury to cells directly
Type III reactions are mediated by what?
Immune complexes, IgG and IgM antibodies bind antigens and the antigen antibody complexes deposit in tissues and induce inflammation.
What mediates Type IV reactions?
Sensitized T-Lymphocytes (TH17 and TH1 cells along with CTLs)
What is the immune mechanism for Type I reactions?
Production of IgE antibody → immediate release of vasoactive amines and other mediators from mast cells; later recruitment of inflammatory cells
What is the immune mechanism for Antibody-mediated (type II) hypersensitivity?
Production of IgG, IgM → binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes
What is the immune mechanism for Immune complex-mediated (type III) hypersensitivity?
Deposition of antigen-antibody complexes → complement activation → recruitment of leukocytes by complement products and Fc receptors → release of enzymes and other toxic molecules
What is the immune mechanism for Cell-mediated (type IV) hypersensitivity?
Activated T lymphocytes →
(1) release of cytokines → inflammation and macrophage activation;
(2) T cell-mediated cytotoxicity
What type of reaction is described by these lesions?
Phagocytosis and lysis of cells; inflammation; in some diseases, functional derangements without cell or tissue injury.
Type II
What type of lesion is described by the following lesions?
Vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation.
Type I
What type of reaction is described by the following lesions?
Inflammation, necrotizing vasculitis (fibrinoid necrosis)
Type III
What type of lesion is described by the following lesions?
Perivascular cellular infiltrates; edema; granuloma formation; cell destruction
Type IV
Name 2 examples of Type II reactions we need to be aware of.
- Autoimmune hemolytic anemia/thrombocytopenia;
- Goodpasture syndrome
Name three examples of type III reactions we covered.
- Systemic lupus erythematosus;
- some forms of glomerulonephritis;
- serum sickness;
- Arthus reaction (in situ dermal injection of antigen).
What are 6 examples of type IV sensitivity reactions?
- Contact dermatitis;
- multiple sclerosis;
- type 1 diabetes;
- tuberculosis;
- rheumatoid arthritis;
- inflammatory bowel disease
A 69 year old woman was stung on her right hand by a wasp. She had been stung several times in the past, most recently two weeks before this sting.
Within 5 minutes she felt faint. She then developed a headache, chest tightness and became unconscious.
She was gasping for air and appeared grey. She regained consciousness in 2 minutes but lost it when she tried to stand. Intramuscular adrenaline and intravenous antihistamines corrected her problem.
•Labs: serum IgE elevated, antibodies to wasp venom elevated, but anti-bee venom normal.
What is the long term treatment modality for this?
Desensitization over 12 weeks followed by monthly maintenance for 3 years.
What are the three changes seen in the immediate or initial reaction to a type I hypersensitivity?
- dilated leaky vessels –> edema
- contraction of smooth muscle
- increased mucus production
Describe the mechanism of the immediate phase reaction.
TH2 activation –> IgE class switch in B cells –> IgE –> release of mediators from mast cells
Describe the late phase reaction mechanism for type I rxns.
Late phase reaction = TH2, epithelial and mast cells secrete IL-5 and eotaxin →eosinophils → enzyme,major basic protein and cationic protein release → tissue destruction
To what receptors on mast cells does IgE bind?
FceRI
What are the common cutaneous manifestations of anaphylaxis?
Urticaria and angioedema
Flushing
Pruritus without rash
What are the common respiratory manifestations of anaphylaxis?
Dyspnea
Wheeze
upper airway angioedema
Rhinitis
What are some common abdominal manifestations of anaphylaxsis?
Nausea
vomiting
diarrhea
Cramping pain
What drug can be useful for peanut allergies?
Omalizumab (Xolair)
What are three high risk groups for latex rubber allergies?
- •patients with spina bifida or multiple urologic procedures
- •health care workers
- •rubber industry workers
What are 5 things that can demonstrate cross reactivity with latex allergies?
- kiwis
- papaya
- banana
- avocado
- melon
- chestnut
Name up to ten things that can cause anaphylaxis
- •Pollens
- •Foods
- •Occupation related
- •Hymenoptera
- •Hormones (autoimmune progesterone dermatitis)
- •Vaccine preservatives
- •Medications, including vitamins and other non-prescribed supplements
- •Local anesthetics
- •Diagnostic agents
Name 8 mast cell secretagogues.
- IL-8
- Codeine
- Morphine
- Adenosine
- Mellitin (bees)
- Heat
- Cold
- Sunlight
How can you have a non-IgE “allergy” or type I reaction?
C5a and C3a anaphylatoxins - release histamine
How many nuclear lobes for eosinophils?
1-2
How many lobes for Neutrophils?
3-4
What mediators vasodilate and increase vascular permiability?
Histamine
PAF
Leuko C4, D4, E4
Neutral proteases that activate complement and kinins
Prostaglandin D2
What mediators cause smooth muscle spasms?
Same stuff as before except for the neutral proteases, quick review.
What causes cellular infiltration?
Cytokines of course
Leuko B4
Eosinophil and neutrophil chemotactic factors
What does in mean if you have a hypersensitivity reaction that is reversible?
Usually only histamine is involved.
What are the hallmarks of Asthma?
Reversible airway obstruction (air trapping)
Hyper-responsive bronchi
Airway inflammation
Uticaria is characterized by dermal hyperpermeability/wheals; so angioedema=
What is an agioedema we must know?
edema of dermis, mucosae and deeper tissues.
Hereditary angioedema- autosomal dominant C1 inhibitor deficiency.
Give some examples of Type I Hypersensitivity disorders?
Anaphylaxis
Bronchial Asthma
Allergic rhinitis, sinusitis
Food allergies
Urticaria
There are some criteria for autoimmune disorders, sorry about the block text but try to talk through them then see what you missed. Just think about autoimmune diseases and how they present.
•Autoantibodies or autoreactive T cells – specific for affected tissue or antigen
•Autoantibodies and/or autoreactive T cells at the site of tissue damage
•Transmissibility to humans or animals
•Reduction of autoimmune response à improvement
•Immunization with autoantigen à induction of autoimmune response à disease
•
•Types II, III, IV hypersensitivities
•Reactions against an individual’s own tissues and cells (autoimmunity)
Placental transfer can accur in autoimmune diseases, match what the IgG Abs are against to the neeonatal disease.
Thyroid hormone receptor
RBCs
Platelets
Acetylcholine receptor
Ro & La
Graves Disease
Hemolytic anemia
Thrombocytopenia
Myasthenia gravis
Cutaneous lupus & heart block
Autoimmune diseases are basically a loss of self tolerance, what are we to always remember when considering pt with an autoimmune disease.
They run in packs so look out for another autoimmune disorder or an increased risk of one.
List the self ag that these diseases are against
Hemolytic anemia
Goodpasture Syn
Myasthenia Gravis
Graves
Hashimoto’s
SLE
Rheumatoid Arthritis
Insulin-dependent diabetes
RBC membrane proteins
Basement membrane ( kidney/lung)
Ach Receptor
TSH receptor
thyroid cells
mult (DNA, nuclear proteins)
connective tissue
pancreatic beta cells
Of course there was talk about MHC and HLA but there were specific diseases that we had to associate with an HLA allele
Rheumatoid arthritis-
Type I diabetes
Ankylosing spondylitis
Postgonococcal arthritis
Autoimmune hepatitis
Primary Sjogren syn
DR4
DR3/4
B27
B27
DR3
DR3
Rheumatoid arthritis, Type 1 diabetes and inflammatory bowel disease all have a gene involved that is non-HLA what is it?
PTPN22- protein tyrosine phosphatase, may affect signalling in lymphocytes and activation of self reactive T cells
IBD (krohns) has another gene associated that Dr Gomez highlighted.
NOD2- controls resistence to gut commensal bacteria
Type II hypersensitivity is Antibody mediated (dependent) meaning it needs an Abs to activate complement or cause cell-mediated cytotoxicity (macros, neutros, eos, natural killer cells)
With this in mind what is the complement part of this reaction most effective against?
Neisseria bacteria
Antibody-dependent cellular dysfunction is when an Ab binding causes abnormal cellular function ie Graves. When is this mechanism normally useful to the body?
Never, 100% pathological
Huge Table on slide 38 pull it up and take a look
test questions on goodpastures syn for sure, non on pernicious anemia
If you have bleeding there are only so many options, decreased production, non functional or destruction of platelets. So how would you test for decreased production?
Look in the bone marrow at the megakaryocytes, if they are absent then there is no production.
If a pt presents with petechia and ecccymosis this bleeding problem, what if you found auto Abs to membrane flycoproteins on platelets and megakaryocytes, what disease should you think of?
Autoimmune thrombocytopenic purpura
What disease does this classically discribe?
Pt is bleeding an alveolar spaces, hemoptysis, SOB, protein in urine, kidney failure (high BUN), hematuria.
Goodpastures- Abs again basement membranes of kidney glomeruli and lung alveoli. The smooth pattern in the picture is characteristic of Goodpastures (Abs spread evenly throughout?)
Type III Hypersensitivity Reactions are Immune Complex mediated. What should pop into your head when you hear type III?
Vasculitis/arthritis predominantly
What is up with serum sickness and why do we care?
Basically you get sick from foreign stuff that you got from someone putting tea in your blood,or horse blood etc. Good news is that it is self limiting.
We care today because it can happen with medications apparently.
He showed a chart where the second spikes of the pt were from the horse ag not the diptheria the pt had, keep that in mind.
So this kid comes in and he has smoky urine and fever (prior sore throat), urine has RBCs and red cell casts (tell us its the kidney not bladder), decreased plasma osmotic pressure and peritorbital edema and you are thinking Goodpastures because of a kidney problem but wait you get this picture, what now?
So now you should be thinking acute proliferative glomerulonephritis because of the lumpy bumpy green picture and the previous infection.
Not sure how complement and Ags get there but there is deposition in the kidney and damage.
Also apparently the periorbital edema is characteristic of this it is unknown why but know it.
A pt comes in with fever, melana with abdominal pain, muscle aches and pains, BP increased,
On exam you find hard little nodules where blood vessels run.
he tell you he had hepatitis B before and you are thinking yeah I know this and you see this picture. Did you have it right?
What is the picture?
What are the nodules?
What is the DDX?
You rock! The picture is fibrinoid necrosis/segmental vasculitis from complement deposition, the hard nodules are the inflamed vessels.
Polyarteritis Nodosa- Multisystem, necrotizing vasculitis of small and medium sized arteries (e.g. renal and visceral).
Pathogenesis- Possibly hepatitis B
–Antigenemia in 10-30%
–B antigen, IgM and complement in vessel walls
When determining pos/neg for a ppd test, what is being measured?
The area of induration - thickened skin patch equal to or greater than 5 mm is a positive test.
What does this PPD test indicate?
measure is 7mm in diameter.
Indicates patient has been exposed to mycobacterium. (Not necessarily TB)
Rheumatoid arthritis is an example of type II and III hypersensitivity. What are three clinical manifestations of this disease?
- Chronic arthritis with inflammation
- Cartilage destruction
- Bone destruction
In MS, what mediates the inflammation? How about the attack on myelin?
Inflammation: TH1 and TH17 cytokines
Myelin destruction: Activated macrophages
What are three clinical manifestations of MS?
- Perivascular Inflammation
- Paralysis
- Ocular lesions
(Demyelination in the CNS)
What are pathogenic T cells specific for in MS?
Myelin Basic Protein
Proteolipid protein
(protein antigens in CNS)
What type of hypersensitivity reaction is DM I?
II
IV
What are pathogenic T cells specific for in DM I?
Antigens of Pancreatic Islet B cells
(Insulin, glutamic acid decarboxylase, others)
What are the principle mechanisms of injury in DM I?
- Destruction of islet cells by CTLs
- T cell mediated inflammation
What are the clinical manifestations mentioned in table 6-5 for DM I?
- Insulitis (chronic inflammation in islets)
- Destruction of B cells
In IBD, the pathogenic T cells are specific for enteric bacteria and self antigens (probably), what mediates this inflammation? What are two clinical manifestations?
TH1 and TH17 cytokines
- Chronic intestinal inflammation
- Obstruction
The T cell target in psoriasis is unknown, and the inflammation is mediated mainly by what?
What is the clinical manifestation?
TH17 cytokines
Destructive plaques in skin
Contact sensitivity (dermatitis) inflammation is mediated by TH1 and TH17 cytokines and targets various environmental antigens. What are the clinicopathologic manifestations?
- Epidermal necrosis
- Dermal inflammation
- Skin rash and blisters
What type of reaction is a granulom characteristic of?
Type IV (likely a test question on this)
•A 47 year old man, presented with a persistent skin rash first noted beneath his ring. Three weeks later he found a similar area on the abdomen.
Diagnosis?
Contact Sensitivity - Type IV hypersensitivity reaction
Must a giant cell be present for a granuloma to form?
No
What do you see in this image?
This section of lymph node shows several granulomas, each made up of an aggregate of epitheliod cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleated giant cells.
Name six organ-specific diseases that are mediated by antibodies.
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenia
- Autoimmune atrophic gastritis of pernicious anemia
- Myasthenia gravis
- Graves disease
- Goodpasture syndrome
Name a systemic autoimmune disease that is mediated by antibodies.
Systemic lupus erythematosus
Name two autoimmune diseases that are organ specific and mediated by T cells.
Type 1 diabetes mellitus
Multiple sclerosis
Name three systemic autoimmune diseases that are mediated by T cells.
- Rheumatoid arthritis
- Systemic sclerosis (scleroderma)
- Sjögren syndrome
Name three organ-specific diseases that are autoimmune in nature?
- Inflammatory bowel diseases (Crohn disease, ulcerative colitis)
- Primary biliary cirrhosis
- Autoimmune (chronic active) hepatitis
Name two systemic autoimmune diseases that are autoimmune in nature.
- Polyarteritis nodosa
- Inflammatory myopathies
A 27 year old woman presents with visual complaints. Nystagmus is evident. She has an intension tremor. Multiple oligoclonal bands are identified in the spinal fluid.
What is the diagnosis?
Multiple Sclerosis
Identify the lesion site in the images. What is the damage we see here? Diagnosis?
Demyelination is visible
MS
Why is this glomerulus lighting up as shown for this SLE patient?
Deposition of IgG antibody in a granular pattern.
What type of lupus nephritis is shown here?
focal proliferative type (class II/III). There are two focal necrotizing lesions in the glomerulus (arrows).
What type of lupus nephritis is shown here?
diffuse proliferative type (class IV). Note the marked increase in cellularity throughout the glomerulus.
What type of lupus nephritis is shown here?
segmental membranous type (class I). Note expansion of basement membrane with “wire looping” and mesangial deposits.
What type of lupus nephritis here?
global membranous type (class V)
A glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes. (Periodic acid-Schiff [PAS] stain.)
What condition do these people have?
What is this symptom?
SLE
Malar Rash
This heart sample came from an SLE patient. What is shown here?
What do the arrows indicate?
Liebman-Sacks endocarditis of the mitral valve
The arrows indicate vegitations attached to the margin of the thickened valve leaflet
What does this person definitely have? What do they likely have?
Definitely: Mikulicz syndrome
Probably (for our purposes anyhow): Sjögren syndrome
What has caused this presentation in this patient with systemic sclerosis?
- The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a claw-like flexion deformity.
- Loss of blood supply has led to cutaneous ulcerations.
What is this condition?
What disease is likely?
Sclerodactyly
Systemic sclerosis
What does this woman have?
Systemic Sclerosis
The image on the left is from normal skin. On the right is from a patient with systemic sclerosis. What are the key findings you see here that point to the diagnosis?
Note the extensive deposition of dense collagen in the dermis with virtual absence of appendages (e.g., hair follicles) and foci of inflammation (arrow).
What is the condition shown here?
Raynauds Phenomenon
–(hyper-reactivity of blood vessels in fingers and hands; blanching when exposed to cold)
What condition are you confronted with here?
Dermatomyositis
What is amyloidosis?
How does it stain?
Any protein that deposits in a beta pleated sheet.
- Congo red stain (Congophilic)
- Apple green birefringence on polarizing
The different types of proteins have different progressions, what are they.
Describe these pictures.
A, A section of the liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids.
B, Note the yellow-green birefringence of the deposits when observed by polarizing microscope.
