immunopathology Flashcards
Describe the 2 types of Type I hypersensitivity
Immediate (type I) hypersensitivity is a rapid immunological reaction within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen.
Anaphylaxis is a systemic form of type I hypersensitivity characterized by shock, edema, and respiratory compromise (due to upper airway edema)
Define Type II hypersensitivity
Antibody-mediated (type II) hypersensitivity is an immunological reaction caused by antibodies against cell surface or extracellular matrix antigens.
Define type III hypersensitivity
Immune complex-mediated (type III) hypersensitivity is a damaging inflammatory reaction to antigen-antibody complexes, especially in blood vessels or glomeruli.
Define type IV hypersensitivity
Cell-mediated [delayed] (type IV) hypersensitivity is an immunological reaction caused by sensitized CD4 T-lymphocytes, sometimes producing aggregates of activated macrophages working together (granulomas).
Anti-cyclic citrullinated peptide (anti-CCP) test=>
Rheumatoid arthritis
Anti-centromere test =>
CREST syndrome
(limited systemic sclerosis)
Anti-Jo-1 (one type of anti-synthetase) =>
Polymyositis / dermatomyositis
Anti-Scl70 (= anti-DNA topoisomerase)
Anti-RNA polymerase (anti-U3 RNP)
Systemic sclerosis
Anti-U1 RNP (anti-RNP not otherwise specified)
Mixed connective tissue disease
Anti-Smith (anti-Sm)
Anti-double-stranded DNA (anti-dsDNA)
Lupus
Anti-nuclear (ANA)
Lupus and many other rheumatic diseases
Anti-SSA (= anti-Ro)
Sjogren syndrome,
neonatal lupus,
subcutaneous lupus
Anti-SSB (= anti-La)
Sjogren syndrome,
neonatal lupus,
subcutaneous lupus
Anti-myeloperoxidase
(= perinuclear anti-neutrophil cytoplasmic, P-ANCA)
Microscopic polyangiitis,
eosinophilic granulomatosis with polyangiitis (Churg
Strauss)
Anti-proteinase-3 (= diffuse cytoplasmic
anti-neutrophil cytoplasmic, C-ANCA)
Granulomatosis with polyangiitis (Wegener’s)
What are 2 drugs that are used for immunosuppressive therapy as well as cancer therapy?
methotrexate
cyclophosphamide.
What is a drug that helps autoimmune diseases and inflammatory diseases?
Corticosteroids
What drugs are given to transplant patients to prevent or treat transplant rejection? Why?
- cyclosporine
- tacrolimus
they block promotion of T cell activation and block secretion of TNF, IFN, IL-2 and IL-4
What allows cyclosporine and tacrolimus to have their speciifc action?
they are calcineurin inhibitors
What are calcineurins?
calcineurin dephosphorylates intracytoplasic nuclear regulatory proteins in lymphocytes which are translocated into the nucleus and activated
this promotes T lymphoctye activations and secretion of TNF, IFN, IL-2 and IL-4
How do cyclosporine and tacrolimus inhibit calcineurins?
by binding to intracytoplasmic receptor proteins called immunophilins which form complexes then bind to and inhibit a calcineurin
How much calcineurin activity is blocked by cyclosporine and tacroliumus?
half the activity at therapeutic levels
must be monitored to determine if levels are therapeutic
What is Mycophenolate mofetil (trade name CellCept)?
reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis (specifically guanine synthesis) that inhibits DNA replication, which inhibits lymphocyte proliferation.
Why would you administer mycophenolate?
treating autoimmune diseases, particularly systemic lupus erythematosus,
preventing and treating transplant rejection.
A patient comes into your clinic and is taking Azathioprine. What is the reason she is taking the medication? How does it work?
has an autoimmune disease or treating systemic lupus erythematosus and/or rheumatoid arthritisa
it is a purine analogue that messes up DNA replication;
A patient comes to your office after suffering from malaria and taking hydroxychloroquine as an antibiotic. The patient notices feeling much better and does not have as much pain in her hands and joints. Why is this?
anti-inflammatory activity
used in treating systemic lupus erythematosus and rheumatoid arthritis.
What drugs would you prescribe someone suffering from an acute phase inflammation reaction? why?
- infliximab,
- etanercept
- adalimumab
block TNF-a
What is Belimumab (trade name Benlysta)?
an antibody to B-cell activating factor.
What would be affected by giving Belimumab?
would not allow the first signal of B cell activation to be given by the
too much BAFF causes abnormally high antibody production causing SLE, RA
A paitent presents with a B cell lymphoma. What drug should you give and why?
Rituximab
an antibody to CD20 on B lymphocytes
A patient presents to your clinic with increased acute inflammation. What drug would you give and why?
Tocilizumab is a new antibody that blocks IL-6 receptors.
Where is CD52 expressed?
high levels by both normal and malignant B and T lymphocytes, with lower levels found on monocytes, macrophages and eosinophils.
Why must a patient who takes a dose of Alemtuzumab be relatively healthy?
powerful immunosuppressant that gives permanent effect likened to AIDS
Define SLE
multisystem autoimmune disease
connective tissue disease that mainly affects the blood, joints, skin and kidneys
What are the 2 major factors in SLE? what do they cause?
genetic => increased risk in family members, genetic links on chromosome 6
environmental=> medications, UV light, estrogen, infections, extreme stress
these lead to destruction of cells leading to Ab directed against nuclear antigens
What are the immunologic factors of SLE?
activaiton of Th cells and B cells, IgG autoantibody production, immune complexes
When will you see pericarditis in SLE?
commonly polyserositis
acute, subacute, chronic
What is the most common gross pathology in SLE?
non-erosive synovitis
What is Libman-Sacks associated with SLE?
1-3 mm verrucous vegetations on either side of valve
What are the 3 most common microscopic pathologic findings in SLE?
- acute necrotizing vasculitis of small arteries and arterioles (with fibrinoid deposits)
- glomerulonephritis in 50% of patients
- cerebritis in 50%
What are the 5 patterns of glomerulonephritis?
- minimal
- mesangial
- focal proliferative
- diffuse proliferative
- membranous
A patient with SLE presents that is in active form in the disease, what would you expect to find?
glomerular granular deposits of IgG and complement
subendothelial dense deposits causing wire loop lesions
diffuse proliferative and indicative of active disease
What are the syptoms of SLE?
- joint pain (90%)
- fever (83%)
- fatigue (81%)
- weight loss (63%)
pleuritic chest pain, photosensitivity, nephrotic syndrome, angina, alopecia, myalgias
What are the signs of SLE?
malar distribution (butterfly rash) causing erythematous skin rash over bridge of nose and cheeks=> 50%
edema occurs in the feet first
blood in the urine
neuropsychiatric
oral ulcers
interarticular skin rash on fingers
peri-ungual erythema around fingernails
alopecia
What are the steps that you would use to diagnose a patient with SLE?
ANA (100% in autoimmune)
anti-ds DNA or anti-Sm antibodies (specific)
What are the hematologic findings in SLE?
- anemia
- thrombocytopenia
are present in 100%
also leukopenia
Other than ANA and hematologic abnormalities, how is the diagnosis of SLE done?
- proteinuria
- urinary red cell casts
- kidney biopsy
- small joint inflammation
- splenomegaly
What is common in pregnancies in SLE?
recurrent spontaneous abortions caused by antiphospholipid Abs
How should you treat SLE?
corticosteroids and immunosuppressive medications
What is the prognosis of SLE?
90% for a 5 year survival rate
80% for a 10 year survival rate
Define sjogren syndrome
autoimmune chronic inflammatory disease of lacrimal glands and salivary glands causing dry eyes and mouth
Describe the primary form of Sjogren syndrome
primary => limited to eyes and mouth => sicca syndrome
- eye involvement called kerato-conjunctivitis sicca
- oral involvement called xerostomia
Describe the Sjogren syndrome in the secondary form
associated with autoimmune diseases
rheumatoid arthritis, lupus, polymyositis, systemic sclerosis, vasculitis, thyroidits
Does Sjogren syndrome only involve the glands?
No
extraglandular involvement of kidneys, joints, skin, muscle, peripheral nerves and brain
What is the common age of a person with Sjogren syndrome?
90% are 35-45 years old
What is the pathogenesis of Sjogren syndrome?
T lymphocyte-mediated immunological attack of some self antigen in ductal epithelial cells of these glands or an antigen in cells in these glands infected by some virus that has a tropism for the epithelial cells of these specific glands.
Why would you think your patient has an increased risk of Sjorgen syndrome?
dry eyes and mouth
enlarged salivary and lacrimal glands
ulcers
Name the micropscopic pathology of Sjorgen’s syndrome
- intense infiltration of CD4 T cells
- destruction of gland architecture with a change in plasma cells, germinal centers
Renal cells can have interstitial nephritis rather than glomerulonephritis
What test would you use to diagnose Sjorgen’s syndrome?
Anti-SSA (Ro)
anti-SSB (La)
What is the best treatment for the primary form of Sjorgen’s syndrome?
topical therapy of dry eyes, dry mouth
systemic cholingergic agents to stimulate secretions
What would you use to treat secondary Sjorgen’s syndrome?
Hydroxychloroquine or rituximab for extraglandular disease
What is the prognosis for Sjorgen’s syndrome?
not a bad prognosis
increase risk for developing lymphoma
Define systemic sclerosis
chronic disease characterized by abnormal accumulation of fibrous tissue in skin and other organs
What is the difference between diffuse and limited sclerosis?
diffuse is widespread skina and early visceral involvement
Limited=> skin of fingers/forearms/face and late visceral involvement
Limited systemic sclerosis is often within the context of CREST syndrome
Who is most likely to get this disease?
highest incidence in 50-60 year old in African american women
What is CREST syndrome?
Calcification, centromere Ab
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasias
What is the general pathogenesis of sytemic sclerosis? specific?
abnormal immune response + vascular damage = increased growth factors for fibrosis
CD4 T cells respond to unidentified antigen release cytokine stimulate fibroblasts to produce collagen
What are the microvascular portions of systemic sclerosis?
intimal proliferation,
capillary dilatation
endothelial injury (increased vWF) and platelet activation leads to fibrosis
Where will you initially see systemic sclerosis?
begins in face and fingers then progresses proximally
What are the most common places systemic sclerosis is present?
skin (100%)
GI (90%)
Why and what type of metaplasia is seen in systemic sclerosis?
Barrett metaplasia => lower esophageal sphincter dysfunction and decreased peristalsis cause gastroesophageal reflux
Fibrous replacement of muscular wall usually in esophagus
