8. Type IV Hypersensitivity Flashcards
Type IV Hypersensitivity: Delayed type hypersensitivity (DTH)
- Involves ____ and ____ immunity
- ____, cytokines and pro- inflammatory mediators
- Reactions ____ or systemic
• Clinical examples:
– Contact ____ test
– Persistent ____ infection
• Antibodies not involved
Hallmark = activation of antigen specific T cells, CD4 - \_\_\_\_ cell or \_\_\_\_ • Presentation of \_\_\_\_ antigen • Cells become activated, produce cytokines, modify or induce an inflammatory rxn by recruiting macrophages or neutrophils • These inflammatory cells cause injury • In addition = CD8 T cells which can recognize processed antigen associated with MHC \_\_\_\_ • Cytotoxic T cells will kill the target cell by inducing \_\_\_\_ • Could be local or systemic • Many forms of DTH ◦ Going to look at contact dermatitis ◦ Persistent intracellular infection: we saw this w/ \_\_\_\_ inflammation
T-cells
cell-medaited
macrophages
localized
dermatitis/tuberculin
intracellular
Th1 Th17 processed class I apoptosis chronic
Type IV Hypersensitivity: Contact dermatitis:
triggered by small molecules > ____ Primary antigen exposure - ____
Contact dermatitis: • DTH that occurs in the skin following contact w/ the antigen • Most of the antigens that cause this disease are \_\_\_\_ • Haptens > can't induce immune reaction > interact with our protein > form \_\_\_\_ > taken up by dendritic cells that reside in epidermis, migrate into draining lymph node > cellular-immune response > \_\_\_\_ lymphocytes (CD4/CD8 cells) that leave the lymph node > produce cytokines that alter \_\_\_\_ permeability • When memory T cells arrive at the scene > first activated by local dendritic cells > takes a few days for reaction to get going **Type I - III are \_\_\_\_ hypersensitivity (minutes - hours) but in type IV, when memory T cells arrive to the scene, they first have to be activated by dendritic cells. This takes a few \_\_\_\_ = delayed type hypersensitivity • First step = processing of antigen, presenting at local site to memory cells, they'll become activated, then they will produce an array of cytokines - either pro-inflammatory or modulate macrophage • Preferentially \_\_\_\_ over neutrophils in these lesions
neoantigen
sensitization
haptens
neoantigens
memory
vascular
immediate
days
macrophages
Th1 derived cytokines activate macrophges—critical to DTH
Activation of ____ cells at local site –> leads to cytokines
• Recruit and activate ____
• Mac’s will produce proteases, pro-inflammatory cytokines (listed), ____ (respiratory burst)
In this situation, there is this ____ antigen
• If the antigen was left alone, it wouldn’t cause any problem
• Rather than be protected (in which case we would refer to it as CMI: cell mediated immunity),
we are dealing with a destructive response (in which case, we will refer to it as DTH)
Th1
macrophages
ROS
inert
Agents that induce contact dermatitis
most are haptens form neo-antigens via modification of self proteins
- Strong detergents or ____
- Skin cleaning products
- Cosmetics or makeup
- ____
- Clothing or shoes
- Household cleaning products
- Formaldehyde and other chemicals
• Rubber or latex • Metals, such as nickel • Jewelry • Perfume or fragrances • Weeds and plants, such as poison ivy or poison oak • Medicinal lotions • Dental materials
* Incomplete haptens, and inert (left alone, they would not do much), but when topically exposed > hapten can combine (reactive to our own proteins) forms \_\_\_\_ (hapten-carrier complex) * Poison ivy - \_\_\_\_ - small molecule on the leaf - some are sensitive to it * \_\_\_\_ can cause reactions, and gold as well * Reaction from socks
soaps deodorant neoantigen catechol amalgams
Clinical signs and symptoms of contact dermatitis
• Skin lesion or rash at the site of exposure
– ____, erythema
– ____ of the skin in the exposed area
– Papules (solid), vesicles, and bullae (fluid filled blisters)
– May involve oozing, draining, or crusting
– May become ____ and thickened, scaly, raw
• Disease: dermatitis; lesion at site, characterized by itching (pruitis) and erythematous • Skin is tender on site of exposure • Solid lesions > papules • Contain vesicles/bulla > fissure bt \_\_\_\_ and \_\_\_\_ > fluid-filled vesicle; vesicle is smaller than \_\_\_\_ ○ Vesicles more often associated with \_\_\_\_ infections, bull more often associated with immune reactions • \_\_\_\_ - not pus! • Indurated and hard, not due to \_\_\_\_
itching (pruritus) tenderness indurated epidermis dermis bulla viral oozing fibrosis
- Catechol is part of leaf > exposed > sensitized > T cells react > formation of complex
- Hypersen > T cells are not reacted to skin by itself, but only if ____ is present (not AID)
- Produce ____ cells > activated > cause damage
- Lesions > you will see ____ cells, ____, ____ (dilated BV)
hapten memory T cytokines inflammation
- Dental pt that was examined wearing latex gloves (left)
- Feet > leather of ____
- ____ clasp reaction
sandals
metal
- ____ can cause reaction, and ____ as well
* Not as bullous as skin lesions
gold
amalgam
Histopathology of Contact Dermatitis
• T cells arrive at local site (starts from dend cells taking up complex, some go to lymph node, but can process \_\_\_\_ > release mediators that start inflam rxn) > BV dilated, and abundance of \_\_\_\_ (not neutrophils) > \_\_\_\_ (BV surrounded by lymphocytes) • No \_\_\_\_ here > just perivascular cuffing • Lymphocytes migrate out of BV into the epidermis > that's where the carrier complex is > in the process: cause damage to epithelium, cause edema in the epidermis > \_\_\_\_ ○ Space bt epithelial cells; formation of spongiotic vesicle (starts off as microvesicle, and eventually gets large) • Hallmark: \_\_\_\_, \_\_\_\_ vesicle, and \_\_\_\_ cuffing (w/o vasculitis)
locally lymphocytes perivascular cuffing vasculitis spongiosis edema spongiotic perivascular
edema
spongiotic
perivascular
- Spongiotic vesicle > larger, and filled with ____
* Nothing more than a ____
fluid
blister
- Blue > stained with reagent that shows T cells; surrounding the ____ and migrating towards the epidermis; encounter ____ cells with hapten carrerir process > spongiosis leads to microvesicles, leads to spongioitic vesicle
- Bulla can be ____ that have fused
BV
dendritic
microvesicle
- Tend to rupture > ulceration > ____ infection
* Treated with ____ lotion (to relieve itching), and if severe reaction > topical ____
secondary
calimi
corticosteroids
• Causes epidermis to slough off > ____ also a problem, in addtion to ____ infection
dehydration
secondary
Type IV Hypersensitivity:
DTH with persistent intracellular microbial infection:
• Viruses:
– ____
– Adenoviruses
– ____
• Bacteria: – \_\_\_\_ spp. – Chlamydia spp. – \_\_\_\_ sppl. – Salmonella spp.
• Fungi: – \_\_\_\_ spp. – Histoplasma capsulatum – \_\_\_\_ – Aspergillus
• Protozoa:
– ____ spp.
– Toxoplasma gondii
– ____ cruzi
• Formation of a \_\_\_\_ • Form of \_\_\_\_ inflammation, but directed by the immune system • Type IV: persistence of pathogen, and it may produce something to make it difficult for inflam response to eliminate it ○ \_\_\_\_ immune response > makes this unique • T cells activated > to a foreign antigen > can produce cytokines > modulate the target cell that's infected (can die), can act on other inflam cells and bring macrophages in, or CD8-cells can be generated to eliminate the antigen ○ Pathogen is \_\_\_\_; the immune system contains instead of eliminates > activates T cells > lesion that walls off infection • Mycobacteria > Tb; 50% of population in US, 33% in world; lack of \_\_\_\_, or people are living much \_\_\_\_; spreads via \_\_\_\_ and exposure to \_\_\_\_
retroviruses
poxviruses
mycobacteria
cornebacterium
candida
cryptococcus
leishmania
trypanasoma
granuloma chronic cellular persistent access closer inhalation conjunctiva
Type IV Hypersensiivity: Tuberculosis
• Etiology: ____ hominis
• Pathogenesis: DTH leading to formation of ____ (tubercles); initially involves ____, but other tissues may be affected
• Signs and symptoms:
– “A ____” that lasts 3 weeks or longer, weight loss, coughing up blood or mucus, weakness or fatigue, fever and chills
• Tx: antibiotics (e.g. ____), drug ____ strains
• Hominis - human strain; bovine strain, reason why milk is homogenized • Initally involves lung; transmitted from infected: cough ○ Starts as pulmonary • Initially, when inhaled > native defense mechanisms: the matter is caught up mucus, brought up by cilia (\_\_\_\_) and you cough it out • Also have \_\_\_\_ macrophage; initially handled, and if it's able to eliminated > no disease ○ Whether or not depends on the \_\_\_\_, the \_\_\_\_ of the strain of myco, and how well the host \_\_\_\_ are able to clear bacteria w/o further activation • Eventually, the bacteria survives (\_\_\_\_), will infect alv macro's intiially, and within a few weeks immunity is developed > T cells arrive and activated produce cytokines, and bc alv macro's are unable to kill internal myco > granuloma forms due to cytokines from T cells > protective mechanism > even with walling out > outcome may be good or bad: wherever the granuloma forms, at expense of normal tissue; in most patients, the myco is eliminated (90%); in subset, the bacteria may be fxnally eliminated, but latent; in even smaller, the disease progresses into Tb • Mycobacterium - \_\_\_\_, not gram+ or gram-
m. tuberculosis granulomas lung bad cough rifampin isoniazid resistant
muco-ciliary escalator alveolar microbial load virulence macrophages
intracellular
acid-fast
Type IV Hypersensitivity
Natural history of Tb
• Progression of Tb from initial infection to onset of clinical manifestations may be viewed as a series of battles between host and organism; outcome depends on:
– ____ of organisms
– Ability of orgnanisms to grow ____ and resist host defense
– Ability of ____ to kill bacteria and immune status of host
• Vast majority of exposed individuals do NOT develop clinical disease; ____ infection (convert to Tb ____)
* Primary infection > develop immunity (DTH) > primary outcome: lesion in \_\_\_\_ (granuloma), and some of bacteria will leave and enter lymph node > another lesion; the primary lesion (pulmonary) and the hialor lymph node > \_\_\_\_ * Three things happen: lesion can \_\_\_\_, and scar tissue; lesion remains, and becomes \_\_\_\_ (these two more common); primary complex will progress into \_\_\_\_ Tb > (most common) initial lesion expands to more in the lung (intrapulm spread) > can lead to \_\_\_\_ spread (via blood) > infect many different organs (spleen bc it's filtering) > develop granuloma thorughout body (\_\_\_\_ Tb) * Latent lesion (walled off by granuloma) > can be reactivated, or reinfected by second \_\_\_\_; can be caused by another \_\_\_\_ (HIV and Tb) > secondary Tb > intrapulm spread leading to homotogenous and miliary Tb (kind of similar to progressive primary Tb) * Vast majority of individuals do not develop symptoms, but will still make you sensitive to TB in the future. This means that even if your TB was cleared by your system, you will still test positive on a TB test. It is essentially just determines that you've been \_\_\_\_
number
intracellularly
macrophage
asymptomatic
positive
lung ghon complex heal latent progressive primary homotegenous miliary
exposure
infection
sensitized/exposed
Type IV Hypersensitivty: Pathogenesis of Tb
* 10% of population will develop \_\_\_\_ or \_\_\_\_ progressive of the exposed population * Alveolar macro > receptors that are non-specfic > recognize \_\_\_\_ and taken up, then the bacteria prolfierates * When super-activated the macrophages have increased \_\_\_\_ activities. The cytokines will also promote the formation of \_\_\_\_.
primary secondary tubercule bacteriocidal granulomas
- ____ cell > eptheloid cell, etc. > all served to wall off
- Left > giant cell, and some epitheloid cells
- Right: granuloma gets larger > undergoes necrosis > ____ necrosis > even when host kills tubercle bacillus > hard to kill bc of the ____ (waxy, lipids) > as they die, the ____ remain
giant
casseous
cell wall
carcasses
- Remember, this is all happening in normal lung.
* Oftentimes, ____ fuse with each other and get bigger and bigger.
granulomas
- Left > ____ necrosis
* Middle > hazy, fuzzy > consolidation, and formation of granuloma; early lesion
caseous
- Mantoux test > ____ injection of protein purified by tubercle baciullus > ____ lesion > took 2-4 days > delayed type hypertension
- No ____, but you will see T cells > will look like ____
- Cannot discriminate bt attenuated strain and ____ strain
- QuantiFERON and T-SPOT = take blood and isolate T-Cell. They then expose the blood to antigen derived from the ____ strain (so it can tell the difference between the attenuated bacteria and the real thing).
- Recently exposed to virulent strain > T cells will be antigenically activated and produce cytokines > newer tests allow ____, but the older tests do not
- Little evidence that the vaccination actually helps
intradermal erythematous granulomas contact dermatitis virulent virulent discrimination
• No vaccination against ____ in US
• If vaccinated, you have been vaccinated with ____ strain (BCG) > bascille cacmette guerrin
• England, in these countries > entering dental class > everyone is ____
• CDC chose not to recommend, bc you lose first ability to ____ bt someone who is infected or not
○ Tb positive > chest ____
Tb attenuated positive discriminate x-ray
