Pathology of Immunity part 2

Question 1

Why would someone do a hematopoietic stem cell transplant

Answer 1

disease process or malignancy that has to do with how our blood cells are produced, so we give ablative regimen to DESTROY THE BONE MARROW.

Then we repopulate with donor bone marrow.

so we clean the slate of the disease –> BRAND NEW IMMUNE SYSTEM

Question 2

Severe combined immunodeficiency (SCID)

Bubble Boy, why is this the name?

can it be in girls too?

treatment?

Answer 2

Bubble –> sever immunodeficiency in both B cells AND T cell due to the defect in T cell function –> fatal if you don’t treat it.

Boy –> X linked. most cases are X linked

there are autosomal recessive forms so you can see it in male and female patients but more commonly seen in boys.

Stem cell transplantation or gene therapy

Question 3

why care about the window period?

Answer 3

blood donations –> we want to make sure they’re HIV free.

we test all HIV for NAT (nucleic acids testing) for the RNA. still you can have a 7-14 day period from exposure.. so it can still happen but it’s rare.

Question 4

When we have declining CD4+ counts, what do we end up getting then? what count would you expect?

what other things would you see in this?

Answer 4

AIDS –> below 200 cells

Opportunistic infections, neoplasms

Question 5

The viral replication in the cell is responsible for the cell death in HIV, what is this called?

what’s another way that the cell can die?

Answer 5

Direct Cytopathic effect

Proptosis –> inflammasome mediated programmed death pathway for cell death in non-replicating viral infection (swelling and bursting)

Question 6

what does amyloid look like on H and E

Where does amyloid tend to manifest?

Answer 6

looks like pink bubblegum that’s sitting in the middle of our cells

Kidney, Liver, Heart, Brain

Question 7

what happens once the HIV makes contact with the mucosal surface?

what is the first thing that happens once the virus gets to the LN and what is this called? when does it happen?

then what happens?

Answer 7

virus goes through mucosal surface –> DCs grab the virus and bring it to the CD4 cells in the Lymph nodes

it’ll start viral replication there in the lymph nodes –>

then there’s a transient period of virus, or a spike, called VIREMIA. –> 7-14 days

SEROCONVERSION –> antibody negative to antibody positive. you are mounting the immune response

Question 8

what are the two ways in which amyloid is created?

Answer 8

the amount of protein production is so high that we can’t deal with it

producing mutant protein that is not capable of being broken down.

Question 9

HIV tropism: it prefers T cells, but what else can it harbor in?

wh

Answer 9

Great hideouts, but you aren’t replicating in them.

Macrophages –> reservoir of HIV in certain tissues, resistant to cytopathic effects

Dendritic cells –> in mucosa, used for transport to lymph nodes where they also can hang out

Microglia –> modified monocytes, live there and have direct access to the CNS, hence why there are neuropathic effects of HIV.

Question 10

What could happen if you have a problem with C1 Inhibitors?

what genotype is it?

what happens normally and what happens when we don’t have this?

are you allergic to something?

Answer 10

Hereditary Angioedema

autosomal dominant

in the normal patient, you have C1 esterase that naturally goes into the complement cascade, particularly creating bradykinin. Normally you have an inhibitor that keeps it from going. No C1 inhibitor means you’re having tons of swelling, particularly in the face, lips, hands, and GI problems.

no, your complement went haywire.

Question 11

Hyperacute rejection:

when does this happen and what happens?

what was the problem that created this?

historically, what incompatibility created this problem?

Answer 11

One of the most dramatic forms of rejection

within minutes to hours kidney gets –> inflammation followed by thrombotic microvasculopathy –> starts to die.

the problem wasn’t that we developed an immune response against the graft, the problem is we HAD ONE READY TO GO.. so mediated by pre-formed antibodies.

AbO compatibility

Question 12

who is at risk for HIV? (5 types)

Answer 12

homosexual/bisexual men

IV drug abusers

Hemophiliacs or people that need blood

Heterosexual contact of the above groups

newborns in areas of high prevalence of women with HIV

Question 13

What are the High yield regions to know in HIV-1?

Answer 13

LTR: initiates transcription, binds transcription factors

gag –> encodes for the PROTEINS inside the virus (including P24)

env (envelope) –> codes for the surface glycoproteins gp120 and gp41

pol (polymerase) –> encodes the viral enzymes reverse transcriptase, integrase, protease

Question 14

Acute Cellular Rejection

1) what mediates this?
2) how can you tell the difference between this and acute antibody mediated reactions?

Answer 14

T cell mediated

this does not stain positive for C4d stain

Question 15

AIDS related lymphomas

Answer 15

HIV allows opportunistic viral infection, including EBV reactivation –> this allows LYMPHOMAS to occur

you can get Burkitts lymphoma, Large B cell lymphoma, KSHV primary effusion lymphomas

Question 16

Acute and Chronic Antibody-mediated rejection:

1) when does each occur?
2) what components are involved in this rejection?
3) what do you see in each case histologically?

Answer 16

occurs downstream.

acute is within 4-5 days to mount the response, chronic can go on for years

Rejection of a graph not through only the B lymphocytes BUT ALSO COMPLEMENT.

you’ll see lymphocytes infiltrating the tubules. and a POSITIVE C4D stain (complement breakdown product)

Chronic –> you’ll see fibrosis with primary effect on the vessels

Question 17

Membrane Attack Complex Deficiency:

what can be affected?

Without this, what happens?

what are patients likely to have because of this? type and specificity

Answer 17

C5,6,7,8,9

without the final MAC, the lysis of the microbial membrane can’t occur.

Neisseria infections –> meningitis

Question 18

Amyloidosis:

what is amyloid?

what do we see on EM?

what are the two types?

Answer 18

something happens resulting a misfolding of proteins and those accumulate and you can’t break them down and that’s amyloid!

you see fibrils on EM that are there forever on.

LOCAL –> neurologic disease giving brain amyloid or tumor that gives amyloid in association

Systemic –> throughout the body through a primary disease (plasma cell disorder) or a Secondary (inflammatory)… and it’s going to accumulate in the kidneys and heart

Question 19

B lymphocytes in HIV?

1) what’s happening with T cells vs B cells?
2) what happens because of these latent infections? what can this present as in patients?
3) what about the Ig’s, what can you get? 3 things.

Answer 19

while we’re killing off the T lymphocytes, we’re actually causing an activation and proliferation of the B lymphocytes –> this is through reactivation of latent viruses like Ebstein Barr Virus

as the secondary infection is present, it proliferates B cells and they can become CLONAL and become a LYMPHOMA, which is a complication of HIV.

you can get a hypergammaglobulinemia that isn’t good for anything really

you get an impaired humoral immunity through a reduced isotope switching and a reduced antibody production.

Question 20

What is the chance of getting HIV from an HIV positive patient?

what about Hep C?

Answer 20

0.3%

30%

Question 21

Common Variable Immunodeficiency (CVID):

1) what does this result in?
2) what do you have to exclude?
3) what 4 things happen because of this?

Answer 21

multiple disorders that result in HYPOGAMMAGLOBULINEMIA

you have to exclude that it’s hyperigm, you have to exclude X-linked agammaglobulinemia

You get recurrent sinopulmonary infections, because of the decreased IgA!!

Granulomas

Chronic diarrhea because of Giardia

Autoimmune disease –> you pretty much have nothing to attack so you attack yourself.

Question 22

DiGeorge Syndrome:

What 4 broad categories of things can you see on individuals with this?

make sure to include the things in each

Answer 22

Facial and Palatal abnormalities –> micrognathia (small chin), shortened philtrum, asymmetry, palatal abnormalities

Cardiac abnormalities –> tetralogy of Fallot, Truncus arteriosis

Tetany –> no calcium because no parathyroid

immunodeficiency –> T cell deficiency. If T cell function is poor, humoral deficiency as well.

Question 23

If someone is rejecting their organ and we treat them, what happens?

What infections are they more susceptible to?

What tumors are more likely to form?

Answer 23

It’s good because we’ve treated them, but we’ve immunosuppressed them by taking out T or B cells

POLYOMAVIRUS in the kidney, cytomegalovirus, fungal and bacterial infections

Tumors –> lymphomas, Kaposi sarcomas, squamous carcinomas (of the skin is more common)

Question 24

Hyper-IgM syndrome:

1) where’s the problem in this case? what is it causing?
2) why is it called hyper-IgM?
3) why is it a problem to have this?
4) how do you treat them?

Answer 24

IT’S ON THE T CELLS –> CD40L is on the T cell, and this is absent/mutated in this case. What happens is we DON’T GET CLASS SWITCHING.

we get way too much IgM and lower levels of other classes.

IgM can’t exactly get the job done with bacteria, so we get encapsulated bacterial infections predominate due to LACK of opsonizing antibodies

Stem cell transplant

Question 25

What is the life cycle of HIV?

1) explain virus replication after attachment and entry

Answer 25

RNA inside the cell needs to go back to DNA.

it uses reverse transcriptase to become dsDNA. Integrase comes along and snips a little gap in the HOST DNA. We insert our HIV cDNA into the HOST DNA until we want to activate

it can be here for a super long time.

Antigenic stimulation causes release of NF-Kb (which normally up regulates the T cell response), but in this case it used a LTR to activate itself. so when NFKB comes in, it wakes up the HIV instead.

LTR activates and causes it to become a vision core structure.

Core structure formed –> kills the cell and releases itself

Question 26

Kaposi sarcoma?

1) what do they present with
2) what is it?
3) what is associated with this tumor?
4) what do you see on biopsy?

Answer 26

they have vivid purple spots all over their body

it’s a vascular tumor

Human Herpesvirus 8 (KS herpesvirus)

proliferation of poorly formed vascular tissues –> spindled nuclei that are stretched out looking.

Extravasation –> RBCs spilling outside of the blood vessel.

Question 27

How does HIV spread?

Answer 27

Sex without a condom

Passed from mother to baby

Parenteral (through a route that isn’t through mucosal stuff) –> Sharing needs or contaminated blood transfusions/organ transplants

Question 28

C1 inhibitor deficiency:

Intestines? ** what do we see on barium X-ray?

Answer 28

corkscrew mucosal folds due to large fold being so edematous

Question 29

Ataxia Telangiectasia:

1) What usually happens first?
2) when you see this, what do you look at?
3) what do they have? what does this lead to
4) what specific cancer is associated with this?
5) what is the problem?
6) genetics?

Answer 29

present with neural signs first –> Ataxic gait, they look unsteady

You look at the eye and see that blood vessels are creeping outwards towards the pupil

IgA and IgG deficiencies –> Sinopulmonary problems, autoimmune disease, and Cancer

Lymphoma

ATM gene mutation –> Defective DNA repair

Autosomal recessive

Question 30

A lot of amyloid in the kidney results in what?

heart?

Answer 30

disrupt the glomerular filtration –> proteinuria –> edema, which is what people present with!

disrupt the myocardium –> affect the conduction –> dysrhythmias occur and that could be the initial presentation

Question 31

what can we do to check if someone has systemic amyloidosis?

what special stain do we do?

what about polarized light?

Answer 31

biopsy of abdominal fat pad –> see if it is positive for amyloid.

Congo red stain –> reddish tinge but still can be confusing, so we can use ….

Congo red + polarized light will give an “apple green” presence of amyloid!

Question 32

why is Male–> Male more likely to give HIV than Male–Female

what introduces viral particles?

Answer 32

the anus is very fragile

vaginal mucosa does tend to tear easily.

breaching the mucosal barrier introduces virus into bloodstream or infects mucosal dendritic cells

Question 33

DiGeorge Syndrome:

1) what is the deficiency and why does this deficiency occur?
2) what organs/structures are present?
3) how can you get it?

Answer 33

Deficiency of T lymphocytes due to failure (partial or total) of PHARYNGEAL POUCHES 3 AND 4

this corresponds with thymus, parathyroids, and heart/great vessels

inherited in sporadic or familial pattern –> many cases are 22q11 deletions

Question 34

What might happen if we get a donor’s hematopoetic stem cell transplant?

what is this mediated by

what 3 manifestations can happen?

Answer 34

we don’t reject the donor because it’s our clean slate, but the donor might reject me.

Graft vs host disease –> mediated by T lymphocytes

skin –> Rash to desquamation

Liver –> Jaundice to cholestasis

Intestines –> bloody diarrhea –> strictures (fibrosis)

Question 35

Treatment for the whole immune response? (immunosuppressive)

What if you want to stop just T lymphocytes in T lymphocyte-mediated cellular rejection?

what about antibody mediated rejection?

Answer 35

corticosteroids

Tacrolimus

Immune globulin, Rituximab (anti CD20 antibody)

Question 36

What is the viral set point?

Answer 36

if you measure the viral load at the time that the latency period is beginning you know how long this period is going to last.

if the viral level is high, the latency period is going to be short

low = can be very long

Question 37

AL is what?

what about AA?

Answer 37

amyloid light chain disease –> immunoglobulin products of the plasma cell disorders churning out amyloid (primary amyloidosis)

AA –> amyloid associated –> chronic inflammation is giving you a secondary amyloid.

Question 38

• Hyperacute rejection
• Acute rejection
• Acute antibody-mediated rejection
• chronic rejection
• chronic antibody mediated rejection

1) which are B cell mediated?

Answer 38

Hyperacute rejection

Acute antibody mediated rejection

Chronic antibody mediated rejection

Question 39

Chronic Granulomatous Disease

Answer 39

neutrophils do not have the toxicity that they have to kill pathogens –> failure of SUPEROXIDE production.

our body recognizes that the neutrophils aren’t doing work –> secondary immune response to WALL OFF the infection

GRANULOMA

Question 40

What is the life cycle of HIV?

1) explain attachment and entry

Answer 40

HIV uses a CD4 molecule for a receptor and the coreceptors CCR5 and CXCR4

the Gp120 on the HIV is going to squat on the CD4 and chemokine receptor (CCR5 or CXCR4) and anchor in

once that has occurred there’s Gp41 that DRILLS through the target cell membrane and inserts its HIV RNA genome!

Question 41

What kind of virus is HIV?

what is it doing?

why is it called a lentivirus?

Answer 41

RNA Retrovirus

RNA virus becoming DNA

“slow” virus.

Question 42

Ebstein Barr virus reactivation for HIV patients leads to what cancer? what do you see in these patients?

Answer 42

hodgkin and non-hodgkin lymphoma –> huge lymph nodes

Question 43

Cervical and Anal cancer is associated with AIDS how?

Answer 43

also viral driven.

HPV –> when you get viral driven cancers and you immunosuppressive someone, you increase the rate of getting HPV.

so unprotected sexual contact increases the chances of having another cancer.

Question 44

Allorecognition?

What are the two pathways associated with it? explain each

Answer 44

our body detecting a grafted organ as foreign and attacking it.

Direct pathway: “I need a kidney, so I’m getting a kidney from a donor, inside the kidney is an APC. this APC. wanders out of the graft and it pokes its head around and says hi, bearing MHC I and II. OUR body senses these MHC and mount the immune response. so a T cell mediated response against blood vessels and renal tubules

Indirect pathway: My APC checks the new graft out and detects the antigens present on the surface of the cells of the graft, processes them like an Extracellular antigen, interacts with CD4 cells, and now we mount a B AND T CELL RESPONSE

Question 45

what’s the difference between AIDS and HIV?

Answer 45

AIDS manifests when you have an infection of HIV and it alters your immune dysfunction to a degree that gives you

1) opportunistic infections
2) secondary neoplasms
3) neurologic manifestations

Question 46

IgA deficiency (isolated)

1) how can it occur?
2) what do we have less defense against? what can that give us?
3) What can people have because of this? why is this happening?
4) how do you prevent this happening?

Answer 46

can occur in both familial and acquired forms.

loss of IgA means less defense against INHALED AN INGESTED PATHOGENS –> sinus, pulmonary infections, UTIs, GI infections.

when you give someone a blood transfusion, there’s a chance they can get transfusion-related anaphylaxis –> because it’s isolated IgA they have antibodies AGAINST IgA

you get blood from IgA deficient donors OR wash out the IgA of blood and then transfuse

Question 47

What’s the synergistic effect of HIV and non-HIV STD’s

Answer 47

if you have unprotected sex with a sore present due to inflammation or ulceration, you’re exposing areas that can get infected by viral particles of HIV

Question 48

X-Linked Agammaglobulinemia:

1) what’s happening?
2) what can’t mature?
3) what are patients at an increased risk of? what about babies?

Answer 48

Defect in Bruton Tyrosine Kinase (BTK) gene on the X chromosome.

you can’t mature beyond the pre-B cell stage.

risk for infection increases after babies lose the maternal antibodies,

we get a lot of ENCAPSULATED bacteria infections –> we need antibodies to interact with these.

Viral infections

Protozoa infections (giardia)

Question 49

over the course of HIV infection, what cells are seen less and less?

Answer 49

CD4 cells

Question 50

Chediak Higashi Syndrome:

1) what’s failing? what does this usually do?
2) what happens because this fails? what do you see more frequently?
3) How can you note this problem in a peripheral blood smear?
4) what can patients present with?

Answer 50

failure of phagolysosomal fusion –> usually this is needed to digest stuff and excrete it.

Ingested pathogen just stays in the cell… so you’ll have increased bacterial infections

you can see the failure of fusion because they have GIANT GRANULES in their neutrophils.. usually they’re fine and dispersed..

white, silvery hair streaks or albinism.

Question 51

How do we test for HIV?

what is the window period? why is it important?

what’s the first thing that’s going to be positive? what test do we do with this? when does this happen?

what’s the second thing that is detected. when does this happen?

what is the third thing that is detected

Answer 51

period of time from exposure and to when a test will become positive –> this is why testing blood kind of sucks.

VIRAL RNA –> Nucleic acid test (NAT) –> 10 days

PROTEIN antigen (p24) –> 15 days?

Antibodies to HIV (you need time to mount the response)

Question 52

What are the important structures that are found on HIV?

there are 4 categories with a bunch of stuff in each.

Answer 52

Capsid proteins –> we test for it. we look for P24 antigen for viremic load

Glycoproteins –> gp120 and gp41 –> important for attachment to target cells and THEY’RE GREAT TARGETS FOR VACCINES.

Viral enzymes –> protease, reverse transcriptase, integrase

HIV-1 RNA genome (gag, pol, env retroviral genes

Question 53

what opportunistic infections can you see?

Answer 53

CNS toxoplasmosis –> lesions in the brain

Pneumocystis jiroveci (carinii) –> fungal infection that looks like a weird pneumonia

Diarrhea –> especially cryptospiridium

Kaposi sarcoma

Question 54

1) What is acute retroviral syndrome? what do people present with this?
2) then typically we see this viremia number shrink drastically, why?
3) what is happening at this time when it’s low and slowly climbing? what is DECLINING?
4) what is #3’s processed called?

Answer 54

this is when there are increasing amounts of viral particles in our system

manifests as a mild flu.. fever, aches, sore throat. this is why people don’t think they have HIV and think it’s just a cold.

It’s feeding into the lymph nodes and leaving the blood, so we won’t see it in the blood! It’s replicating in the lymph nodes.

CD4 cells are declining

Clinical latency –> silent massacre of CD4 cells that lasts for YEARS without symptoms

Question 55

how does the mother transfer HIV to the child? (3 ways)

Answer 55

in utero through placental –> fetal transfer of the virus

while born through genital secretions

or through breast milk

Question 56

Kaposi Sarcoma can also cause what 2 diseases?

Before aids, what did this present in? why do we care?

Answer 56

Primary effusion lymphoma –> fluid accumulation in the lung, you see large immature lymphocytes that stain positive for KSHV

Castleman’s disease (disease of lymph node swelling)

old mediterranean men. it shows that opportunistic infections happening in aids patients

Question 57

Wiskott Aldrich Syndrome:

1) what is the problem?
2) what is the triad to know?
3) what’s the treatment?

Answer 57

WASP gene mutation

Thrombocytopenia (low platelets), Eczema, Recurrent infections (due to BOTH T cell loss and hypogammaglobulinemia)

Stem cell transplant