Immunopathology (hypersensitivity, autoimmunity, immunodeficiency, transplant rejection)
Terms in this set (155)
innate immunity recognizes
PAMPs by TLRs
acquired immunity has
acquired immunity is split into
1) humoral (B cells, Ig)
2) cell-mediated (T cells, macrophages and CT cells)
MHC class I
found on all nucleated cells
MHC class II
on antigen-presenting cells via the Th cells
primary lymphoid tissues
thymus = T cells
bone marrow = B cells
secondary lymphoid tissues
lymph nodes, where immune response occurs
pathway after antigen exposure
antigen exposure --> goes to lymph node --> processed antigen and random encounter --> B and T cells proliferate --> differentiate --> effector cells and memory cells --> go to periphery --> local site
What are atopics?
people who produce too much IgE, which will stick to mast cells, and causes lots of sensitization (1st exposure). During the second exposure there will be an explosive mast cell degranulation
What happens during sensitization?
NOTHING! Just 1st exposure that leads to Ig
What happens as a result of mast cells?
degranulation --> histamine --> vasodilation --> edema, eosinophils --> PGs and LTs --> cytokines
What are the primary mediators produced by mast cells/basophils?
What does histamine cause?
- muscle contraction
- vascular permeability
- secretion by nasal, bronchial, and gastric glands
What are the secondary mediators produced by mast cells/basophils?
- lipid-derived (AA) mediators:
- leukotrienes (vascular permeability and muscle contraction)
- prostaglandins (bronchospasm and mucous secretion)
- platelet-aggregation factor
- cytokines in late phate
Immune mechanism for type 1?
IgE production --> mast cells --> mediator release --> LESION (dilation, edema, contraction, mucous)
hallmarks of type 1
systemic type 1 disease is
local type 1 diseases are local becuase
the response location depends on where the antigen is
- antigens: pollen, foods, drugs, and insect venom
- pruritic elevated areas on skin (either red or white with red border)
- EDEMA OF SUPERFICIAL DERMIS (where BV are)
- lesions appear rapidly and fade within hrs
- very closely related to uriticaria
- DEEPER EDEMA - edema of both dermis and subcutaneous fat (lips, tongue, and eyes)
Allergic Rhinitis/allergic conjunctivitis (hay fever)
- affects 20% of population
- antigens: pollen, fungi, animal allergens, dust mites
- causes mucosal edema, redness, and mucous secretion (red eyes, tearing up)
- causes secretions and mucosa containing numerous EOSINOPHILS
Atopic Asthma (extrinsic)
- due to environmental antigens (dust, pollens, foods)
- hallmarks: reversible airway obstruction, bronchial constriction, more mucous secretion, chronic inflammation with eosinophils
- morphology: overdistended lungs, occlusion of bronchioles, edema, more glands
what are the three phases of asthma?
asthmatic antigens stimulates what?
hyper IgE production and Type 1 rxn
Acute phase of asthma
- mast cell degranulation leads to mediators
Chronic phase of asthma
- eosinophils, basophils, neutrophils, monocytes, lymphocytes
- damage to epithelium by proteins from eosinophils
- smooth muscle hypertrophy
- DESTRUCTION OF AIRWAY
in asthma, what would cause the small lumen of the airway?
- thickened basement membrane
- more mucous
- hypertrophy of muscle
- hyperplasia of glands
histo of early lesions of asthma
- dilated vessels
histo of chronic lesions of asthma
- more mucous
- thicker basement
- more muscles
- bigger glands
- more macrophages and neutrophils
Systemic anaphylaxis is characterized by:
- widespread edema
- respiratory distress
- vascular shock
- location-dependent (hives in skin, bronchoconstriction in lungs, obstruction of larynx, cramping of GI, hypotensive shock of vascular)
what does epinephrine do when in anaphylactic shock?
- smooth muscle relaxation
- prevents degranulation
how to prevent anaphylactic shock in your chair?
- take histories - atopics, allergies
- stop the triggering event (IV or oral drug)
- know medications and smoking
- have emergency protocol - epinephrine
what do you do during the acute emergency of anaphylaxis?
what is the pharmocologic treatment of anaphylaxis?
2) theophylline - increases cAMP to shut off degranulation of mast cells
3) corticosteroids and antihistamines after pt is stabilized
how do you prevent anaphylaxis?
- avoid the antigen (take history)
- cromolyn sodium to block degranulation
- hyposensitization - pt gets sensitized by allergen as therapy
- puncture/prick test
- tests for various allergens
C3a - degranulation
C5a - degranulation
C3b - opsonization --> phagocytosis
What are the 3 mechanisms of type 2?
1) antigen on host cell --> IgG or IgM --> C3b --> phagocytosis
2) complement mediated lysis --> pores on host cells --> cell dies of shock
3) ADCC = IgG binds to host cell --> NK binds to Fc region on IgG --> NK releases factors for cell apoptosis
what are the two agents in NK that lead to apoptosis?
1) perforin (lets granzyme enter cell)
2) granzyme (kills the cell)
Why wouldn't ADCC work for red blood cells?
Because ADCC induces apoptosis and apoptosis only occurs on nucleated cells
What are isohemogluttinins?
Describe each blood type, antigens, and antibodies
Type A = A antigen, B antibody
Type B = B antigen, A antibody
Type AB = A,B antigen, no antibody, universal acceptor
Type O = no antigen, AB antibody, universal donor
What kind of Ig are the isohemogluttinin antibodies? What is the significance of this?
They are IgM which do not require T cells to be activated. This means that B cells can produce IgM without T cell help
Why don't you have A antibody if you're type A?
how do we get sensitized to other types of blood antigen?
naturally via bacteria
What is the result of a mismatched blood transfusion?
- ANTIBODY-MEDIATED agglutination of the new RBC leads to blockage of vessels
-lysis of the new RBC leads to release of hemoglobin
What are the clinical manifestations of mismatched blood transfusion?
1) mild fever and chills
2) acute kidney failure or blood in urine
3) vascular collapse or death
4) DIC (which can result in hypercoagubility and infarction OR hypocoagubility and spontaneous bleeding
Rh factor carries what antigen?
Under what circumstance would Erthyroblastosis fetalis occur?
Mom is Rh-
Dad is Rh+
fetus is Rh+
2nd fetus or later
Mechanism of Erythroblastosis fetalis?
- mom develops Ab to babies D antigen
- IgG develops from Th + B cells
- IgG is able to cross the placenta and destroys blood cells of fetus using complement
Presentation of erythroblastosis fetalis in fetus?
- brain problems
Rh immune globulin; attaches to the + Rh antigen and prevents the mother's immune response
Some treatment for hemolytic disease of newborn
- decrease levels of IgG in mother
- blood transfusion for severe anemia in baby
- IV fluids for low bp of baby
- phototherapy to reduce biluribin
Breakdown of red blood cells leads to release of _____ which leads to two things:
leads to jaundice or kernicturis --> damage to brain
antibody excess and antigen excess conditions leads to formation of
soluble small complexes - these are the problem
where do small soluble complexes accumulate?
1) turbulent flow
3) fenestrations/filtration (glomerulus)
What's the main mechanism for type 3?
complexes accumulate --> activate complement --> gap formation --> phagocytes release lysosomal enzymes --> can't get to soluble complexes --> neutrophils damages endothelium --> VASCULITIS --> vessel undergoes necrosis
what is the overall effect of the renin-aldosterone-anginin process?
increased blood volume
increased cardiac output
In type 3, WHAT'S THE DIRECT CAUSE OF INJURY
What Ig's are involved in Type 3?
IgG and IgM
what is glomerulonephritis and what types of hypersensitivity are involved?
destruction of the glomerulus
type 2 or 3
- proteins in horse serum induced Ab response leading to immune complex formation
- symptoms: arthritis, rash, fever
pathogenesis of serum sickness
- necrotizing vasculitis
- fibrinoid necrosis
what kinds of lesions form on the skin due to serum sickness?
histo of serum sickness
- lots of neutrophils
- DESTROYED BV, no blood
- necrosis of tissue
histo of kidney of serum sickness
- early would have complexes and neutrophils
- protein and blood in urine
histo of lung of serum sickness
- thick alveolar septa
immunofluorescence of type 3
- what is the antigen?
- what is the appearance?
- antigen is C3b, IgM, or IgG
- appearance is LUMPY BUMPY
What is the arthus reaction?
- this is a localized reaction that occurs at the site of injection of horse serum
- activates complement, brings neutrophils, and destroys the dermis
- you see a "skin lesion"
histo of arthus reaction?
hypercellular with neutrophils
- antigen = streptococcas antigens
- pathogenesis - impetigo, lots of immune complexes, hypercellular glomerulus
clinical manifestations of poststreptococcal glomerulonephritis?
- hematuria (blood in urine)
- red cell casts
- mild hypertension
histo of poststreptococcal glomerulonephritis?
- LUMPY BUMPY FLUORESCENCE
treatment of poststreptococcal glomerulonephritis?
- antibiotics to eliminate residual bacteria
- anti-hypertensive meds to control edema and HTN
- low salt
- conservative care
5 types of hypersensitivity pneumoitidies (which exhibit extrinsic allergic alveolitis)
1) farmer's lung
3) pigeon breeders lung
4) mushroom pickers lung
5) detergent workers lung
Farmers lung pathogenesis
- IgG mediated
- complement --> alveolar macrophages --> release chemotactic factors for neutrophils
Farmer's lung signs and symptoms
- flue like syndrome
- develops within hours
- symptoms resolve quickly
- recurs with re-exposure
treatment of farmer's lung
antigen avoidance and corticosteroid therapy
histo of lung of farmer's lung
- necrotic tissue
- LUMPY BUMPY FLUORESCENCE
what's a neoantigen?
hapten + protein carrier that initiates type 3 immune response
two types of Type 4 rxns
1) contact dermatitis - due to exposure to haptens
2) persistent intracellular infection - Tb, chronic inflammation, round cells
summary of contact dermatitis
hapten-carrier complex is picked up by dendritic cells of epidermis --> carried to dermis --> lymphatics --> lymph nodes --> activates T cells --> lymph nodes make memory and effector cells --> blood --> increase vascular permeability --> T cells bring macrophages --> epidermis gets damaged
What does CD4 do?
CD4 --> cytokines --> macrophages --> tissue injury
What does CD8 do?
CD8 --> apoptosis
What is contact dermitis triggered by?
What cells get activated in contact dermatitis?
Th1 derived cytokines activate macrophages, this produces damage
What isn't contact dermatitis sustained?
because the antigen will run out eventually - antigens are usually natural things (poison ivy, etc)
Clinical signs of contact dermatitis
- skin lesion/rash at site of exposure
- pruritus, erythema
-vesicles and bullae (blistering)
- blisters appear wet
- indurated (hard) blisters
what is pruritis?
What is spongiosus?
edema in the epidermis, big space in histo
What is spongiotic vesicles?
bigger spongiosus that results in blisters
histo of contact dermatitis
edema, vesicle, T cells cuffing, blistering
what's the bad thing about epidermis sloughing off?
if leaves skin behind vulnerable to secondary infection
What's the hallmark of Tb?
formation of granuloma
what leads to the formation of a granuloma in Tb?
DTH --> persistent activation of T cells and cytokines eventually leads to formation of granuloma. Granuloma tries to wall off the infection but granuloma impedes pulmonary tissue function
What's the human strain of Tb called?
M. tuberculosis hominis
Signs and symptoms of Tb
- bad cough that lasts longer
- weight loss
- coughing off blood or mucous
- fever or chills
What tissues does Tb infect?
first lung then spreads to other tissue
What's the treatment of Tb?
What is the drug resistant strain of Tb?
when people don't complete the Ab cycle and you get Tb strains that are drug-resistant
What's the pathway of primary complex of Tb?
primary complex (Gohn's complex) either leads to 1) dormant complex or 2) progressive primary Tb --> spreads outside lung --> MILIARY TB
What's the pathway of secondary Tb?
dormant granulomas persist --> dormant granulomas reactivate --> secondary Tb --> progressive secondary Tb --> MILIARY TB
What is miliary Tb?
Tb that spread to other tissues
What happens when granulomas coalesce?
the coalesced granuloma --> caseous necrosis in the lung which destroys functional lung tissue
What are two types of Tb tests?
1) skin test = Mantoux test, if sensitized, you'll develop delayed-type contact dermatitis, rash
2) Blood test = T-SPOT or QuantiFERON
Autoimmune diseases involve what type hypersensitivity?
What's a requirement for autoimmune disease?
What are three common autoimmune diseases?
thyroid disease, diabetes, and SLE
Is autoimmune disease organ specific or non-organ specific (systemic)?
How can autoimmune diseases occur?
- genetics (HLA genes regulate immune response)
What's a disease is associated with a certain HLA allele?
- delete a bad T or B cell by apoptosis
- if it's messed up, an auto-reactive lymphocyte can gain access to the peripheral circulation
- this is how we suppress auto-reactive cells that made it past central tolerance
1) suppression - Tregs prevent activation
2) deletion - apoptotic signal is sent to cell
3) anergy - antigen triggers OFF SIGNAL in the cell
What are sequestered self-antigen?
they're antigens that we never develop tolerance to because we aren't exposed to them, they either live:
- physical barrier - blood brain barrier
- immunologically privileged site - eye antigens are away from immune system
two ways autoimmunity can occur:
1) breaking self-tolerance
2) sequestered self-antigen is exposed
How can we break tolerance?
- mutation of T/B cells lead to autoreactive cells
- altered activity of Tregs
- estrogen = immuno-enhancers
- tissue injury
- change the self-antigen itself by mutation
- antigenic mimicry - antigen looks like a self-antigen
- maturation (development) antigens
Various types of autoimmunity
- cell mediated injury (type 4) - diabetes
- immune cytotoxic reactions (type 2) - pemphigus vulgaris
- immune complex reactions (type 3) - SLE
- receptor stimulation (graves)
- receptor blockage (Myasthenia gravis)
- action of autoAb
- antigen = intrinsic factor for B12 absorption
- autoAb blocks binding to vitamin B12 and blocks binding of complex to Cubam
- symptoms - lack of B12, megablastic anemia, regular anemia, weakness
- lots of LARGE megakaryocytes
- PMNs become hypersegmented
- RBC = oval and egg-shaped
Autoimmune Hemolytic Anemia
- action of autoAb
- clinical symptoms
- antigen - neoantigens on RBC like drugs
- autoAb (IgG or IgM) removes RBC by lysis or phagocytes
- symptoms - jaundice, tiredness, increased heart rate, dyspnea
- warm agglutinins (IgG) --> hemolysis and opsonization
- cold agglutinins (IgM) --> Raynaud's phenomenon
- treatment - blood transfusion, steroids, immunosuppressants
What is raynaud's phenomenon?
- in the cold, low blood flow --> less oxygen to tissues --> cyanotic tissue
- cold agglutinins can cause clots, which decreases blood flow
- autoAb action
- antigen is membrane glycoprotein IIb/IIIa complex (platelet-related)
- autoAb is IgG and IgM and they destroy platelets by removal and agglutination
- symptoms - low platelets, more megakaryocytes in bone marrow to compensate, petechiae, purpura, mucosal bleeding, bleeding into vital organs
- action of autoAb
- antigen = acetylcholine receptors at post-synaptic muscle membrane
- autoAb decreases functional receptors by destroying or blocking
- symptoms - low neuromuscular transmission, high fatigued muscles, pharyngeal and respiratory problems, opthalmic problems (diplopia and ptosis)
- treatment - anti-cholinesterases, immuno therapy, plasmapheresis and IV-Ig
what is diplopia?
what is ptosis?
- action of autoAb
- antigen = TSH receptor
- action of autoAb - TGI binds to TSH receptor, so thyroid thinks it has to make more T3/T4 --> constant stimulation --> goiter/thyroid enlarges
- symptoms - HYPERTHYROIDISM, low TSH levels, goiter, exothalmos, weight loss, excitable, nystagmus, tremors, muscle wasting, tachycardia
- hyperplastic thyroid - not inflammation
- treatment - adDress symptoms, thionamides (to inhibit TSH synth), radioiodine ablation, removal of thyroid gland
what is exopathlmos?
what is nystagmus?
rapid eye movements
In Grave's disease, what are the levels of T3/T4? TSH? TQQQQQQ
- action of autoAb
- antigen = thyroglobulin
- autoAb - ADCC (complement)
- DTH - T-cell infiltration of thyroid, cytotoxic T cells
- symptoms - goiter, elevated TSH, HYPOTHYROIDISM, fatigue, cold, weight gain, slow reflexes, puffy face
- histopathology - lots of lymphocytes and plasma cells, lots of eosinophils
- treatment - thyroid hormone replacement therapy
In Hashimotos Thyroiditis, what are the levels of T3/T4? TSH? TQQQQQQ
- action of autoAb
- antigen = anti-strep Ab which is ANTIGENIC MIMICRY to glycoproteins in heart and joints
- carditis - type 2 response to tissue on myocardium
- happens at 5-15 and then at 25-35 y/o
- symptoms - acute - chest pains, palpatations, dyspnea, carditis, Aschoff bodies, fibrinous pericarditis
- symptoms - chronic - valvulitis (murmur due to incompetent valves), myocarditis (leads to CHF)
histo of acute rheumatic fever
- aschoff bodies = granuloma, giant cells
- Anitsckow cells - snake eye cells in the aschoff bodies
- action of autoAb
- antigen = basement membrane collagen
- autoAb = IgG does type 2 reaction, brings neutrophils
- symptoms - glomerulonephritis, hematuria, renal failure, lung hemorrhage
- SMOOTH AND LINEAR immunofluorescence
histo of glomerulus of goodpasture syndrome
- blood in tubules/urine
- eventually just gets destroyed
histo of lungs of goodpasture syndrome
- alveoli filled with red cells
Insulin Dependent Diabetes Mellitus (type 1, juvenile)
- antigen - pancreatic beta cells, insulin
- pathogenesis - T cell infiltrate leads to insulitis (lesions on islet cells), autoab don't do anything
- symptoms - accumulation of glucose, hyperosmolality, hyperkeratonuria, polyuria (pee out excess glucose, feel hungry, weight loss)
- complications - renal faiure, atherlosclerosis, periodontitis, Mucor (fungal infection leads to lesions)
histo of insulin dependent diabetes mellitus
- lymphocytes in islets of langerhans
- CD4, CD8, macrophages
- INSULITIS OCCURS
What causes injury in insulin dependent diabetes mellitus?
- antigen = probably alpha-fodrin
- pathogenesis - T cells infiltrate --> necrosis of lacrimal and salivary glands, autoab don't do anything
- symptoms - in older women, xerostomia, parotid gland enlargment, fissured tongue, sicca (dry eyes)
- diagnosis - take a lip biopsy, minor salivary glands
- treatment - supportive, artificial tears and saliva
histo of Sjogren Syndrome
- early = T cells, intact ducts
- later = fibrosis, lots of T cells, non-functional ducts
Sjogren's syndrome has a 5-15% chance of becoming:
low grade non-Hodgkin B cell lymphoma (Cancer) within glands
SLE - Systemic Lupus erythematosus
- renal symptoms
- antigens - ANAs, lymphocytes, erythrocytes, platelets, coagulants
- etiology - infection, estrogen, drugs, stress
- pathogenesis - immune complex formation, photosensitivity
- symptoms - malar rash (butterfly), photosensitivity, plaques, ORAL ULCERS***, arthritis, renal, antibodies against platelets, myocarditis, tachycardia, abnormal ECG, CNS (seizures or pscyhosis), fatigue, fever, myalgia, weight loss
- renal symptoms - proteinuria, HTN, insufficient kidney, thickened capilarries, smudgy, red and white cell casts in the urine
photosensitivity in SLE
light --> cell injury --> cell dies and releases DNA --> inflammation by injury --> DNA gets into blood --> immune complexes form in blood --> inflammation --> neutrophils --> DESTROY BV (vasculitis) --> microthrombi form and fibrinoid necrosis
necrosis from immune reactions (vasculitis or endocarditis)
immunofluorescene of SLE
- LUMPY BUMPY
- the antigen isn't fixed but they do form along the epidermal junction due to sunlight
diseases that show glomerulonephritis:
2) serum sickness
3) poststreptococcal glomerulitis
- when blood is drawn, the SLE patients have the LE cell
- when you draw blood, white cells normally get damaged. If you find the autoAb attached to these damaged cells, the person has an autoimmune disease involving ANAs
Chronic Discoid Lupus
- difference to SLE
- antigen - unknown, possibly ANA
- pathogenesis - immune complex formation
- symptoms - coin like lesinos from sunlight, erythmatous plaques on face and scalp
- NO SYSTEMIC COMPLICATIONS
- results in
- antigen - IgG
- pathogenesis - autoAb is rhematoid factor (TF) immune complex in synovial lining --> inflammation
- Th1 --> cytokines --> inflammatory cells
- Th17 --> neutrophil invasion
- Pannus formation - inflamed lining that keeps getting larger --> destroys cartilage and bone --> pain and low motility, finger disfigurations