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
MS age of onset is typically between childhood and 50 yrs, affects women 2x more often than men, and oddly the incidence increases proportionally with distance from the equator.
What are the frequent clinical patterns seen in this disease?
What is the hallmark sign?
Hallmark sign is the presence of oligoclonal immunoglobulin bands in CSF.
Clinical pattern often includes:
- Unilateral visual impairment
- Ataxia
- Nystagmus
- motor and sensory problems
- Poor bladder control
What is the genetic component in MS?
Poor balance between effector and protective T cells
How is the initiation of pathogenesis in MS begun?
•CD4+ TH1 & TH17 react with myelin antigens and secrete cytokines; leukocytes recruited –> demyelination
What are the gross and micro pathological findings that one finds in MS?
Gross
- Firm plaques
- optic nerve
- brain stem
- paraventricular
Micro
- Monocytes
- Lymphocytes
- Lipid laden macros around vessels
- gliosis
- A 14 year old boy awoke with mild weakness in his legs. His symptoms worsened and the next morning he complained of weakness of his arms.
- A lumbar puncture was performed after admission to a hospital.
- No cells; slight increase in protein
- Nerve conduction studies à demyelinization
- Antibodies to ganglioside
- History of influenza 2 weeks before onset of symptoms
- Returned to normal 8 days later
What is the diagnosis?
Guillain-Barre Syndrome
Guillain-Barre Syndrome often begins after an infection or vaccination, may present with ascending paralysis and sensory loss. What mediates the damage seen in this condition?
What does the damage look like?
T Cell mediated peripheral nerve demyelination, which shows up as segmental demyelination of peripheral nerves, with axon damage in severe cases.
What is the mechanism behind rheumatic fever?
Molecular Mimicry, due to streptococcus infection. The antibodies that develop to the M component react against host tissues, particularly the heart, but is a multisystem disorder.
What are some tell tale clinical pearls that can point to rheumatic fever?
- Prior sore throat
- Pericardial rub present
- Heart Failure
- Arrythmias
- Positive antibody tests for…
- ASO (antistreptolysin)
- Anti-DNAse B
Why is it that patients who have had a rhuematic fever episode are commonly placed on chronic antibiotic use?
Since the patient will have memory B cells, if they should again contract a strep infection, their body will resume antibody production and once again attack itself.
What are the three carditises that are seen in rheumatic fever?
Which is most clinically important?
- pericarditis
- myocarditis
- endocarditis (Most clinically important)
In rheumatic fever induced pericarditis, autoantibodies bind to components of pericardium and induce acute inflammation. Leading to what?
Fibrinous bread and butter pericarditis
In rheumatic fever induced myocarditis autoantibodies bind to myocardial antigens result in degeneration of stroma with lymphocytes and activated macrophage accumulation around blood vessels.
What is this accumulation called?
What are mononuclear activated macros called?
- Aschoff Bodies
- Anitschkow cells
What does Rheumatic fever induced endocarditis lead to?
- Degeneration of stroma and inflammation of heart valves with fibrinous vegetations, usually at valve closure
- Later get fibrosis of vegetations, inflamed valve structures, and chordae tendinea (rheumatic valvular disease)
In addition to the carditus stuff rheumatic fever can present with what additional three things?
- •Migratory arthritis – swollen, red, and tender joints that occur in succession
- •Subcutaneous nodules
- •Skin Rash called erythema marginatum
In chronic rheumatic valvular disease, what five things might we see on the mitral valve?
What three things on the aortic valve?
Mitral
- •Scarring and thickening of leaflets
- •Chordae tendineae become incorporated into valves
- •Fusion of commissures
- •“Fish Mouth” deformity
- •May show stenosis or regurgitation/insufficiency (or both)
Aortic
- •Fusion of commissures
- •Secondary dystrophic calcification
- •May show stenosis
When we hear connective tissue diseases, what should we think?
Autoimmune diseases
In connective tissue diseases lab tests with a wide variety of autoantibodies and antinuclear antibodies will usually be positive.
What antibody pattern is most common but least specific?
What might a nucleolar pattern indicate?
How about a centromere pattern?
What pattern is always present in mixed connective tissue disease?
What antibody pattern is most common but least specific?
- Specklyed = non DNA (SS-A, SS-B, RNP, SM)
What might a nucleolar pattern indicate?
- 60% of scleroderma, or a small population of SLE patients
How about a centromere pattern?
- CREST Syndrome
What pattern is always present in mixed connective tissue disease?
- Peripheral or circumfrential (RIM) staining = dsDNA
Homogenous or diffuse nuclear staining patterns indicate antigens including chromatin, histones and dsDNA are involved. What diseases are associated?
SLE
Drug induced lupus
A speckled pattern nuclear stain reveals involvement of non-DNA nuclear constituents suce as SM antigen, ribonucleoprotein, and SS-A/SS-B reactive antigens. What diseases are associated with this?
(6)
- SLE
- Rheumatoid arthritis (RA)
- Systemic sclerosis (SS)
- Neonatal lupus
- Cutaneous lupus
- Sjogren syndrome
What would a nucleolar pattern indicate the antigen would be?
What is the associated disease?
RNA
Systemic Sclerosis (SS)
What kind of nuclear staining pattern would be associated with CREST syndrome?
What antigen?
Centromeric Staining Pattern
Centromeres
What autoantibodies should tip you off that the patient has SLE?
Anti-double stranded DNA: 40-60%
Anti-Sm (Smith antigen): 20-30%
What autoantibodies should tip you off that the patient has Drug induced LE?
Antihistone >95%
What autoantibodies should tip you off that the patient has Limited scleroderma-CREST?
Anticentromere 90%
What autoantibodies should tip you off that the patient has Sjögren Syndrome?
SS-A (Ro) 70-95%
SS-B (LA) 60-90%
What is the nature of the antigen in Sjögren Syndrome?
RNP
What autoantibodies should tip you off that the patient has systemic sclerosis-diffuse?
Scl-70: 30-70%
What is the nature of the antigen in systemic sclerosis-diffuse?
DNA topoisomerase I
What autoantibodies should tip you off that the patient has Autoimmune Myositis?
Jo-1 25%
- 26 year old woman with fatigue and painful, stiff joints of 4 weeks duration
- 6 year history of Raynaud phenomenon. She developed a blotchy rash on the bridge of her nose after sunbathing
- Has bilateral knee effusions but no muscle tenderness, proteinuria or fever
- Decreased platelets and lymphocytes
- Positive ANA (IgG, homogeneous) and anti ds DNA
- Negative C-reactive protein, rheumatoid factor, and anti-extractable nuclear antigens (SS-A and SS-B)
- Decreased C3 and C4
- Increased IgG and normal IgA & IgM
- Skin biopsy: granular deposits of IgG and complement at dermal/epidermal junction
- Improved over 4 weeks & was symptom free for 5 years. Subsequently a rash developed on hands & thighs (acute vasculitis?) and Raynaud phenomenon worsened
What is the diagnosis?
SLE - Key info is the anti ds DNA
What are the features of systemic lupus erythematosus?
- Most common form
- Attacks skin
- Attacks internal organs
What are the features we should know about chronic discoid lupus erythematosus?
- Confined to skin
- May develop into SLE later
What features should we be aware of with regard to subacute cutaneous LE?
- Widespread superficial non-scarring lesions
- Mild systemic symptoms
What features of drug induced LE do we need to know? What drugs induce it?
- Usually resolves with removal of meds
- Medications that commonly induce are:
- hydralazine
- procainamide
- isoniazid
- D-penicillamine
What features should we know regarding neonatal LE? What antibodies are involved?
- Usually transient
- due to antibodies crossin the placenta
- Systemic involvement can be clinically systemic
Antibodies = SS-A (Ro) and SS-B (La)
SLE is a chronic multi-system autoimmune disease which may affect any system of the body, but most commonly affects what five things?
- Joints (90%)
- Kidneys (75%)
- Heart (40-50%)
- Serosal Surfaces
- Brain
The pathogenesis of SLE arises due to the presence of susceptibility genes plus environmental factors, leading to abnormal immune responses.
What are four ways in which SLE impacts the immune response?
- •Activate innate immunity (dendritic cells)
- •Lower threshold for activation of innate immunity
- •Ineffective regulation of T cells
- •Reduce clearance of immune complexes and apoptotic cells
A person is said to have SLE if any 4 or more of what 11 criteria are present?
- Malar rash
- Discoid Rash
- Photosensitivity
- Oral Ulcers
- Arthritis
- Serositis
- Renal disorder
- Neurological disorder
- Hematologic Disorder
- Immunological Disorders
- Antinuclear Antibody
What are two examples of neurological disorders that apply to the classification of SLE?
Seizures or Psychosis - in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)
What are four hematologic disorders mentioned in the diagnostic criteria for SLE?
- hemolytic anemia
- leukopenia
- lymphopenia
- thrombocytopenia
What are two immunological findings that Dr. Gomez pointed out in the criterion for diagnosis of SLE?
Anti-DNA antibody to native DNA in abnormal titer, or
Anti-Sm-presence
What is a malar rash?
Discoid rash?
Malar - Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Discoid - Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Which of the clinical and pathologic manifestations of SLE did Dr. Gomex indicate were of highest yield?
- Hematologic
- Arthritis, Arthralgia or myalgia
- Skin
- Renal
- Raynaud Phenomenon
What hypersensitivity types are involved in SLE?
III - immune complex deposition in vessels, glomeruli, etc.
II - Auto antibodies to blood cells = phagocytosis and lysis
Tissue binding antibodies = tissue damage
SLE is characterized by antibodies against self antigens. One of these is an Ab against phospholipids. What is this commonly called? What does it cause?
Lupus anticoagulant (which actually causes coagulation in the body. hooray!)
Causes Anti-phospholipid syndrome
- Thrombotic microangiopathy
- Recurrent miscarriages
What kind of kidney function test result abnormalities might you see in SLE?
Increased Serum Creatinine
RBCs and RBC casts in the urine
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
How do we treat SLE?
- Corticosteroids
- “other” immunosuppressants
- Chemotherapy drugs such as cytoxan
- A 52 year old woman consulted an oral surgeon because of dry mouth. The only abnormality was an elevated erythrocyte sedimentation rate. Six months later she complained of sore eyes.
- Laboratory testing
- Rheumatoid factor +
- Increased IgG and IgM, normal IgA
- Positive Schirmer test
- Her rheumatoid factor has increased over the years.
- Developed positive ANA, anti Ro and La.
- Bilateral polyarthritis developed in her hands, wrists and knees.
What is the condition? How do you know?
Sjӧgren Syndrome
Dry mouth, sore eyes
+ for ANA, Anti Ro and La
What doesmikulicz syndrome refer to?
Enlargement of the lacrimal and salivary gland (specifically the parotid apparently) from any cause.
Often seen in Sjӧgren Syndrome
What are two characteristic presentations of Sicca syndrome?
- Keratoconjunctivitis sicca = dry eyes with blurred vision, thick secretions in conjunctival sac
- Xerostomia = dry buccal mucosa, difficulty swallowing, buccal fissures
What does this person definitely have? What do they likely have?
Definitely: Mikulicz syndrome
Probably (for our purposes anyhow): Sjögren syndrome
What is a test you can do for Sjögren syndrome?
Schirmer Test
•A 35 year old woman complains of polyarthralgia. She feels that the skin of her hands face has tightened over the last 6 months. You observe that the skin of her hands and face is thick and normal folds are lost. There are telangiectasias. Her fingers are ulcerated and have subcutaneous calcification. She has had difficulty swallowing, chest pain and painfully pale extremities in the cold.
Diagnosis?
Systemic sclerosis (P.K.A. Scleroderma)
Systemic sclerosis is characterized by fibrosis and ischemic changes brought on by vessel changes.
What are the pathological changes we see both microscopically (5) and grossly (2)?
Micro
- –Initial stage of infiltration by cells and edema
- –Increase in collagen in the dermis
- –Thinning and atrophy of the epidermis
- –Dystrophic calcification may occur
- –Arteriolar intimal thickening
Gross
- –Mask-like face
- –Sclerodactyly
What organ systems are affected in systemic sclerosis?
- GI tract, most commonly esophagus
- Kidneys
- Lungs
- Heart
What changes to the esophagus are seen in systemic sclerosis? (4)
- –Muscle layers replaced by fibrous tissue
- –Inflexible, rigid tubes
- –No peristalsis
- –Acid reflux when GE junction affected
What changes are seen in the kidneys of a patient with systemic sclerosis?
Is the damage to the kidneys in systemic sclerosis due to immune complex deposition?
- –Intimal proliferation and thickening of arteries à Ischemia
- Damage not due to immune complex deposition
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).
The CREST variant of systemic sclerosis is a more benign version, and usually does not have visceral involvement. What does CREST Stand for?
–Calcinosis (calcium deposits in skin)
–Raynaud phenomenon (hyper-reactivity of blood vessels in fingers and hands; blanching when exposed to cold)
–Esophageal dysmotility
–Sclerodactyly
–Telangiectasias (small abnormal clusters of tiny vessels in the skin)
What is the condition shown here?
Raynauds Phenomenon
–(hyper-reactivity of blood vessels in fingers and hands; blanching when exposed to cold)
In CREST syndrome, What antibody will be positive?
Anti-Centromere Antibody
What condition are you confronted with here?
Dermatomyositis
Dermatomyositis is an autoimmune disease affecting the skin and skeletal muscle, as the name implies. What are the clinical features to know?
- –Bilateral, symmetric, proximal muscle weakness
- –Increased serum creatine kinase
- •Rash typically on face, usually affecting the eyelids (heliotropic rash)
- •Dermatomyositis often associated with occult tumors
What is part of the initial workup of the dermatomyositis patient?
Search for malignancy! It is offten associated with occult (hidden) tumors.
What lab results will you get if you test for antibodies in dermatomyositis?
–ANA is positive
–Antibody to tRNA synthetase called anti-Jo-1, in less than half
What is polymyositis?
Autoimmune disease involving skeletal muscle without skin involvement.
What are the mechanisms of transplant rejection?
T cell Related
Antibody mediated
What are the three T cell related mechanisms of transplant rejection?
Cytotoxic T lymphoctes –> parenchymal & endothelial cell injury
CD4+ –> delayed hypersensitivity reactions
CD4+ –> activation of macrophages
What are the four types of transplant rejection?
- Hyper acute
- Acute cellular
- Acute Humoral
- Chronic
What goes down in hyperacute rejection of transplants?
Preformed anti-donor antibodies are already present. This leads to rapid destruction of the tissues. This is pretty rare now-a-days
In acute cellular (direct pathway) rejection of transplants what happens?
T cells of the recipient recognize allogeneic (donor) MHC molecules on the donor’s APC’s
In acute humoral rejection of transplants, what happens?
Exposure to the class I and class II HLA antigens of the donor graft may evoke antibodies and attack graft vessels (vasculitis).
What goes down in chronic rejection of transplants (indirect pathway)?
recipient T cells recognize MHC antigens of the graft donor after they are presented by the recipient’s own APCs
What goes down in chronic rejection of transplants (INdirect pathway)?
circulating antibodies cause vascular injury in graft
What do we need to be concerned with when considering a bone marrow transplant?
Rejection, possibly in the form of graft Vs. host disease
What is graft vs. host disease?
Immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, if the graft recognizes the host as foreign, the host has pretty much no defense.
Can Graft Vs. host disease happen with other transplants besides bone marrow?
Yes, but quite rare. Due to the presence of local immune cells still in the transplanted tissue.
If you have T cell defects, what should you worry about from bacteria, viruses and Fungi/parasites?
Bacteria
- Bacterial sepsis
Viruses
- Cytomegalovirus
- epstein-barr virus
- severe varicella
- Chronic respiratory and intestinal viruses
Fungi and Parasites
- Candida
- pneumocystis jiroveci
If you have B cell defects what should we worry about regarding bacteria, viruses and fungi/parasites?
Bacteria
- Streptococci,
- staphylococci,
- Haemophilus
Viruses
- Enteroviral
- encephalitis
Fungi and Parasites
- severe intestinal giardias
What bacteria and fungi/parasites are problematic if you have granulocyte defects?
Bacteria
- Staphylococci
- pseudomonas
Fungi/Parasites
- Candida
- Nocardia
- Aspergillus
What should we expect to colonize someone who has complement defects?
Neisserial infections, other pyogenic infections
What bacteria and fungi/parasites are problematic for those who have phagocyte defects?
Bacteria
- Staphylococci
- Serratia
- Listeria
Fungi/Parasites
- aspergillus
- candida
If someone has deficiencies in C1, C2 or C4 what consequences do they face?
- little or no increase in susceptibility to infections
- Can develop SLE-like autoimmune disease
What consequences befall them who are deficient in C3?
- serious and recurrent pyogenic infections.
- immune complex-mediated glomerulonephritis
If someone had a deficiency in any of the following, what would be the major problem?
C5, 6, 7, 8, or 9
These form the attack complex.
See recurrent neisserial (gonococcal and meningococcal) infections
What does a defect in c1inh lead to?
- hereditary angioedema induced by stress or trauma
- episodes of edema affecting skin and mucosal surfaces
- life-threatening asphyxia
- nausea, vomiting, and diarrhea
- Rx - C1 inhibitor concentrates
What do SCID diseases have in common?
- Defects in humoral and cellular immunity
- Thrush (oral candidiasis), diaper rash, and failure to thrive
Sorry for the block text, tell me what you know in general about SCID?
•50%–X-linked defect in ȣ-chain receptors for interleukins
•Decreased T-cells
•Low immunoglobulins
•40%–autosomal recessive
•Adenosine deaminase (ADA) deficiency
•Maternal T cells can cross placenta and attack the fetus (GVH) disease
•Morbilliform rash shortly after birth
•Hypoplastic thymus
•Low or absent lymphoid cells
•Atrophic lymph nodes
•Lymphopenia
Rx – Bone marrow transplant or gene therapy (can develop T-cell leukemias
X-linked Agammaglobulinemia is also called what?
Infections begin in males at about 6 months with no B cell maturation past a pre B cell stage, what is the mechanism of this?
Brutons Disease
•Bruton tyrosine kinase mutation stops immunoglobulin maturation after heavy chain rearrangement
What cells population changes would you see in Brutons disease.
- Decreased B cells
- Poorly developed germinal centers
- No plasma cells
- No intestinal IgA (Giardia infections)
- No Igs for opsinization of organisms (encapsulated bacteria)
- Normal T cells
- Rx- injected immunoglobulins
What is the mechanism behind DiGeorge Syn/Thymic Hyperplasia?
How would it present?
abnormal 22q11
- Thymus, parathyroids, some of the clear cells of the thyroid, and ultimobranchial body defects
- Hypoparathyroidism with hypocalcemia can lead to tetany
- Cardiac outlet defects
- Facial abnormalities
- broad nasal bridge, long face, narrow palpebral fissures, micrognathia
- Viral, fungal and protozoal infections
- Similar features to severe combined immunodeficiency
- T-cell deficiency in thymus, spleen and lymph nodes
Hyper IgM Syn talk it through, nothing bolded here so just logic it.
What is the major problem with this syn?
- 70% X linked/30% autosomal recessive
- Recurrent pyogenic infections in a child 6 months or older
- Have IgM but do not get class switching
- Inability of helper T cells to induce IgG, IgA, and IgE formation
- Genetic defect = usually CD40L
- Usually can’t make IgG for opsonization of bacteria
- Small lymph nodes without germinal centers
- Autoimmune hemolytic anemia, thrombocytopenia, and neutropenia
Opsinizing bacteria, no IgG
How does Common Variable Immunodeficientcy present?
What do the cell populations look like?
- M=F
- Children or adults with a history of recurrent infections involving the lungs, bronchi, ears or sinuses
•Recurrent herpesvirus infections
- Absent plasma cells (maturation blockage)
- No immunoglobulins
- Normal numbers of other B cells
What is Isolated IgA syn and how does it present?
- Failure of terminal differentiation
- Low levels of secretory and serum IgA
- Usually asymptomatic but may have
- Sinopulmonary infections
- Diarrhea from intestinal infections
- Anaphylactic transfusion reactions to IgA in donor plasma
- Immune disorders such as SLE and RA
Wiskott-Aldrich Syndrome has what gene mutation?
What does this mutation cause?
How does it present?
•WASP (Wiskott-Aldrich syndrome protein) gene mutation
- X-linked defect in protein linking cell membrane to cytoskeleton
- Thymus starts morphologically normal but there is progressive secondary depletion of T lymphocytes
- Patients do not make antibodies to polysaccharide antigens, and the response to protein antigens is poor (Encapsulated Bacteria Major Trouble)
- Thrombocytopenia, eczema & recurrent infections
- Petechiae or purpura, hematemesis or melena, epistaxis
- Recurrent infections, ending in early death (from 8 months to 6 years now)
Tell me about Ataxia Telangiectasia.
- Autosomal recessive
- Abnormal ATM gene which normally detects dsDNA breaks
- Occular and skin vascular malformations (telangiectasias)
- Neurologic defects
- Abnormal gait (ataxia)
- Increased sensitivity to radiation
- Increased incidence of neoplasia
- Breast and hematopoetic malignancies
- Immunodeficiency
- Deficiency of isotype switched antibodies (IgG2, IgE and IgA)
- Respiratory infections
Here are some secondary (acquired) Immunodeficiencies
Name the mechanism that goes with the cause below.
Human immunodeficiency virus infection (AIDS)
Irradiation and chemotherapy treatments for cancer
Involvement of bone marrow by cancers (metastases, leukemias)
Protein-calorie malnutrition
Removal of spleen
Chronic infections
Acute disorders (massive burn)
Diabetes mellitus
Chronic uremia
Depletion of CD4+ helper T cells
Decreased bone marrow precursors for all leukocytes
Reduced site of leukocyte development
Metabolic derangements inhibit lymphocyte maturation and function
Decreased phagocytosis of microbes
Bone marrow suppression, etc.
Numerous defects.
Neutrophil dysfunction
T-cell dysfunction and neutrophil dysfunctions, decreased immunoglobulins
Describe the stages of HIV infection?
Acute
Middle chronic
AIDS
- Infection of memory CD4+ T cells (which express CCR5) in mucosal lymphoid tissues and death of many infected cells.
- Acute retroviral syndrome similar to flu for a few weeks about 3-6 weeks post infection
- Lymph nodes and the spleen have continuous HIV replication and cell destruction
- Mostly clinically asymptomatic for years
- Prolonged by HAART (highly active antiretroviral therapy)
•Fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and secondary neoplasms or <200 CD4+ T cells/mm3 of blood
There is a table on slide 142 with all the AIDS defining conditions he said we had to know, I am including the bolded ones.
Cervical Cancer (invasive)
Encephalopathy HIV related
Kaposi sarcoma
Lymphoma (burkitt, immunoblastic, brain)
Wasting Syn attributed to HIV
There is a ton of abnormalities with HIV try to talk them through by category
Lymphopenia
Decreased T cell function in vivo
Altered T cell function in vitro
Polyclonal B cell activation
Altered monocyte or macrophage function
Table 6-14. Major Abnormalities of Immune Function in AIDS
Lymphopenia
Predominantly caused by selective loss of the CD4+ helper T-cell subset
Decreased T-cell Function in Vivo
Preferential loss of activated and memory T cells
Decreased delayed-type hypersensitivity
Susceptibility to opportunistic infections
Susceptibility to neoplasms
Altered T-cell Function in Vitro
Decreased proliferative response to mitogens, alloantigens, and soluble antigens
Decreased cytotoxicity
Decreased helper function for B-cell antibody production
Decreased IL-2 and IFN-γ production
Polyclonal B-cell Activation
Hypergammaglobulinemia and circulating immune complexes
Inability to mount de novo antibody response to new antigens
Poor responses to normal B-cell activation signals in vitro
Altered Monocyte or Macrophage Functions
Decreased chemotaxis and phagocytosis
Decreased class II HLA expression
Diminished capacity to present antigen to T cells
The AIDS related malignancies were listed before, see if you can rememeber most of them.
Kaposi sarcoma (Human herpesvirus 8)
Non-Hodgkin lymphomas -
Burkitt lymphoma (EBV)
Immunodeficiency-associated large B-cell lymphoma (EBV)
Primary CNS lymphoma (EBV)
Other B-cell lymphomas (clonal proliferations + DNA glitches)
Cervical cancer/dysplasia (HPV types 16, 18, etc.)
Squamous cell carcinoma of anus (HPV)
Squamous cell carcinoma of vulva (HPV)
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.
What is the major fibril protein in primary amyloidosis?
Associated diseases?
What is its precursor protein?
AL
monoclonal plasma cell proliferations
Immunoglobulin light chains, chiefly gamma type.
Secondary amylodosis fibril ?
Associatied diseases?
Precursor?
AA
Chronic inflammatory conditions
SAA
Hemodialysis associated amyloidosis fibril
disease?
precursor
AB2m
Chronic renal failure
B2-microglobulin
Systemic senile amyloidosis fibril
disease
precursor
ATTR
Transthyretin
1- medullary carcinoma of thyroid precursor
Calcitonin
2-Islets of Langerhans precursor
Disease
Islet amyloid peptide
Type 2 diabetes
