I18

Question 1

What is transplant rejection?

Answer 1

Transplant rejection is the destruction of grafted tissue by the acquired immune system of the recipient host. The immune response that destroys grafted tissue is directed at unique determinants that arise due to genetic differences between the donor and the recipient.

Question 2

What does ‘allogeneic’ mean?

Answer 2

describes individuals of the same species that are genetically different.

Question 3

What is an autograft?

Answer 3

a graft of tissue from one part of the body to another part of the body. The tissue is genetically identical to the recipient (because the recipient is also the donor) and the tissue should not rejected. This is also known as an isograft.

Question 4

What is an syngeneic graft?

Answer 4

one in which the donor and the recipient are genetically identical (e.g. identical twins). No rejection should be expected.

Question 5

What is an allograft?

Answer 5

a graft between two patients that are not genetically identical. This graft will be rejected unless appropriate immunosuppressive drugs are used appropriately in the recipient.

Question 6

What is a zenograft?

Answer 6

a graft between two different species. This will certainly be an allograft as well.

Question 7

What are alloantigens?

Answer 7

antigen which varies between members of the same species

Question 8

What are alloreactions?

Answer 8

mmune responses directed against alloantigens

Question 9

Allogeneic solid tissue grafts (e.g. a kidney) are destroyed (or rejected) primarily by what?

Answer 9

T cells that have specificity for alloantigens on the grafted tissue

Question 10

What can occur during a bone marrow transplant?

Answer 10

Sometimes T cells from the grafted bone marrow attack alloantigens of the host. This is called graft vs. host disease (GVHD) and it results in inflammatory responses in the skin and in the gastrointestinal tract, primarily.

Question 11

Can GVHD occur following a solid organ transplant?

Answer 11

Yes, If there are mature naïve T cells in the vasculature of the organ that is transplanted, those T cells an enter secondary lymphoid tissues of the recipient. If any of them have specificity for any peptide derived from the recipients tissues, they can be activated, resulting in what is essentially an autoimmune condition (GVHD).

Question 12

T or F. Slloreactions that can occur following a blood transfusion do not involve T cells

Answer 12

T. This should make sense because RBCs do not produce MHC class I or MHC class II.

Question 13

What antigens are the primary targets of alloreactivity following a blood transfusion?

Answer 13

The A, and B blood groupNOTE: Normal flora bacteria produce molecules that are almost identical to the A, B, and O antigens

Question 14

What is the “O” antigen composed of?

Answer 14

from the RBC membrane there is a membrane ceramide molecule attached to:glu-gal-GalNac-Gal (with Fuc) side chain

Question 15

What is the composition of the “A” antigen?

Answer 15

core is same as O antigen with added GalNAc added to terminal Gal

Question 16

What is the composition of the “B” antigen?

Answer 16

core is same as O antigen with added Gal added to terminal GalTherefore, all of us express the O antigen, thus, we are all tolerant to that structure and will not make an antibody response that is specific for the O blood group antigen. In contrast, the A and B blood group antigens are different, and people that do not produce the A or B blood group antigens will have antibodies specific for the A or B antigens, respectively, in their blood. A person with type AB blood will not have antibodies specific for any of the blood group antigens in their circulation.

Question 17

A person with type O blood would make antibodies against which blood types?

Answer 17

A, B, and AB

Question 18

Which blood types would make antibodies against type O blood?

Answer 18

None (the best donor)

Question 19

A person with type A blood would make antibodies against which blood types?

Answer 19

B. And vice-versa

Question 20

A person with type AB blood would make antibodies against which blood types?

Answer 20

None (the best recipient)

Question 21

What are Rh factors?

Answer 21

Alloantigens (other than the A and B blood group antigens) that are expressed on RBCs that must be considered prior to a transfusion.There are around 50 distinct Rh factors, but there is one that is clearly the most important (RhD).

Question 22

A person that has never had a transfusion should not have ever mounted an antibody response to any of the Rh factors. Why?

Answer 22

there are no normal flora pathogens that produce structures that are similar to Rh factorsTo ensure that patients never do make these responses, RhD is considered before giving a transplant to ensure that they will not be exposed to Rh factors that they do not express.

Question 23

What is the universal donor type?

Answer 23

O-

Question 24

What is the universal recipient?

Answer 24

AB+

Question 25

What is hyperacute rejection?

Answer 25

Hyperacute rejection is mediated by pre-formed antibodies that are specific for alloantigens that are expressed on the grafted tissue. The most common cause of hyperacute rejection is transplantation of tissue from a donor whose blood type is not compatible with the recipient’s. The same rules apply for transplantation of tissue as applies for blood transfusions.

Question 26

T or F. Vascular endothelium expresses the same blood group antigens that are found on the surface of that person’s RBCs

Answer 26

T. So, if tissue from a person with type A, B, or AB blood is grafted into a person that has type O blood, and therefore has anti-A and anti-B antibodies, those antibodies will bind to the A and B antigens expressed on the vascular endothelium of the grafted tissue, initiating the complement cascade and promoting phagocyte influx into the tissues. As the phagocytes recognize the Fc regions of antibodies and complement opsonins via their Fc and complement receptors, respectively, they produce inflammatory mediators. Platelets will bind to the activated endothelium, resulting in occlusion of small vessels. Overall, this inflammatory response kills the grafted tissue within 48 hours in most cases.THIS is hyperacute rejection

Question 27

What is Acute transplant rejection mediated by?

Answer 27

typically mediated by CTL that have specificity for alloantigens of the grafted tissue.

Question 28

What are the targets of CTLs in acute transplant rejection?

Answer 28

These alloantigens are (almost) always the products of polymorphic genes. The MHC class I and class II genes are the most polymorphic genes in our genomes, and allogeneic MHC molecules are almost always the targets of CTLs in transplant rejection.

Question 29

How can acute transplant rejection be avoided?

Answer 29

The recipient should have no pre-formed immune responses to any of the alloantigens on the donated tissue. The recipient has to prime the response after the graft is introduced into the recipients body. This typically takes 11-15 days for tissue to be rejected after transplantation. Of course, this assumes that no anti-inflammatory drug treatment is being administeredaka first set rejection

Question 30

What is second set rejection?

Answer 30

If a second skin graft is performed between the same donor and recipient strains as shown on the last panel, with the recipients being mice that have already rejected the same skin transplant following a previous engraftment, rejection of the allogeneic tissue will occur much more quickly following the second grafting procedure. This is because the recipient has already generated a memory T cell response to the alloantigens of the donor tissue and has produced a clonally expanded pool of memory CD8 T cells that can be more more efficiently and quickly activated upon secondary exposure to those same alloantigens, resulting in more rapid rejection (4-7 days). This is known as second-set rejection.

Question 31

How are naïve T cells presented alloantigens following an allogeneic transplant?

Answer 31

1) APCs from the donor tissue can migrate into secondary lymphoid tissue of the recipient. Because these APCs express the same alloantigens (MHC class I-derived peptides, primarily) of the donor tissue, these allogeneic peptides will be presented to naïve T cells of the host, priming a CTL response to the donated tissue.2) Recipient APCs will also take up pieces of grafted cells that have died and will be able to present determinants of the donor tissue to naïve T cells in the secondary lymphoid tissues.So, there are two mechanisms for priming this response.

Question 32

The chances of successful transplantation can be vastly improved by ensuring the best possible MHC haplotype match between a recipient and the tissue donor.

Answer 32

Matching is performed based on a combination of serological studies and DNA-based techniques to determine the degree of match between the recipient and the potential donors.

Question 33

What are the most important HLA loci for graft compatibility?

Answer 33

For reasons that are not completely understood, degree of matching at HLA-A, HLA-B, and HLA-DR loci appear to be the most important for a successful tissue transplant.Please remember that anti-inflammatory drug regimens are also extremely important to the success of transplantation of any tissue that has allogeneic determinants.

Question 34

It is possible for grafted tissue between donor and recipient that have an identical MHC haplotype to be rejected. How?

Answer 34

There are polymorphic genes in our genome other than the MHC class I and MHC class II genes. These are called minor histocompatibility antigens. Several minor histocompatibility antigens are also encoded within the MHC locus.

Question 35

What is the time frame for rejection based on histocompatibility antigens?

Answer 35

Rejection that occurs due to responses directed solely against minor histocompatibility antigens takes significantly longer than typical acute rejection. In the absence of anti-inflammatory drug treatment, minor histocompatibility rejection takes between 30 and 60 days.

Question 36

___ transplants do not require HLA-matching.

Answer 36

Liver. For some reason, the liver is refractory to acute rejection…this is not well understood. However, blood type matching is critical to prevent hyperacute rejection.

Question 37

What other type of transplant doesn’t require HLA matching? Why?

Answer 37

Corneal transplants also do not require HLA matching and, in fact, no anti-inflammatory drugs are needed to prevent rejection. Because the cornea is not vascularized, CTLs cannot gain access to the cornea and cannot cause damage to a transplanted tissue.

Question 38

Why is the fetus not rejected by the mother during pregnancy? Unless the father has an identical MHC haplotype to the mother, the fetus is certain to be essentially an allograft for the pregnant woman.

Answer 38

Here are a couple of things that are known: (1) The placenta is fetal tissue and it does not express MHC molecules. Therefore, it may serve as a partial barrier to the mother’s T cells. (2) It also turns out that the placenta and the uterine epithelium produce Th2 cytokines that down regulate cell- mediated immune responses.

Question 39

How much of the population doesn’t express RhD? Consequence?

Answer 39

Approximately 15% of the population does not express RhD, and since they do not express the proteins in their tissues, they will not be tolerant to RhD and will potentially make an immune response specific for RhD if they ever encounter the antigen in sufficient concentrations (such as through a blood transfusion).

Question 40

An RhD- women that becomes pregnant must always be concerned about the potential that she is carrying an RhD+ fetus for two reasons:

Answer 40

During childbirth, there is always a backwash of fetal RBCs into the mother’s circulation. When this occurs, the mother will almost always prime a full blown B cell response to the RhD factor. This memory response will result in the production of RhD-specific IgG antibodies that will cross the placenta during any subsequent pregnancy. If she later carries a fetus that is RhD-positive, maternal antibodies will bind to the fetal red blood cells causing their destruction, causing what is known as erythroblastosis fetalis or hemolytic disease of the newborn.AND If the mother sustains a minor injury (during any pregnancy with an RhD- positive fetus) that causes fetal blood to get into the mother’s circulation (not uncommon), she will make the anti-RhD response during the pregnancy.

Question 41

How can we prevent a mom from making an anti-RD antibody response?

Answer 41

injections of a product known as RhoGAM (a preparation of anti-RhD IgG antibodies) are given to the mom. These antibodies will rapidly bind to and cause the destruction of any fetal RhD-positive RBCs that get into the mother’s circulation, preventing the mom from making an anti-RhD response.

Question 42

What are some symptoms of erythroblastosis fatalis?

Answer 42

1) In addition to the anemia that results from destruction of RBCs, the child also develops immune complex disease as a result of all of the antigens (released by destroyed RBC) that rapidly become part of immune complexes. 2) Enlargement of spleen and liver 3) Petechial lesions due to the depletion of platelets that results from excessive platelet adherence to the walls of small blood vessels (mediated by macrophage derived TNF-alpha production).

Question 43

When/ In what situations should RhoGAM be given?

Answer 43

From a theoretical point of view, RhoGAM should only need to be administered to RhD-negative mother that are carrying an RhD-positive child that has a blood type that is compatible with the mother’s blood type.If the blood types are incompatible and the mother has antibodies in her circulation that will bind to fetal RBCs, RhoGAM is really not needed because the mother has her own RhoGAM. For instance, if the mother has type A blood (and therefore has anti-B antibodies in her circulation), and if the child has AB-type blood, the mother’s anti-B antibodies will bind to any fetal RBCs that get into her circulation and mediate their rapid destruction, preventing her from making an RhD-specific antibody response.Unfortunately, in most circumstances the physician will not know the fetus’s blood type. Therefore, RhoGAM is always given to RhD-negative mothers during pregnancy (starting at the beginning of the 2nd trimester, I believe) with a bolus immediately following childbirth as well.

Question 44

What is graft vs. host disease (GVHD) again?

Answer 44

The major cause of morbidity and mortality following a bone marrow transplant.This condition develops when mature T cells from the grafted tissues become activated and then “attack” host tissues. Mature T cells from the graft were negatively selected in the donor, so when they are transplanted into the recipient, there would be some of them that have specificity for alloantigens of the recipient. These T cells migrate into the secondary lymphoid tissues of the recipient where they sample peptide MHC complexes on recipient APCs. If they become activated, they proliferate and differentiate into effector cells. If they have specificity for a recipient cell determinant, they will perform their effector function causing either cell death or inflammation.In contrast to solid organ transplants that are damaged by T cells that have specificity only for the grafted tissue, GVHD primes a T cell response that has specificity for determinants that are potentially expressed all over the body of the recipient.

Question 45

Please remember that GVHD can also be a consequence of solid organ transplant, but the incidence is much lower than in more marrow transplantation.

Answer 45

Please remember that GVHD can also be a consequence of solid organ transplant, but the incidence is much lower than in more marrow transplantation.Very uncommon in kidney transplant

Question 46

GVHD typically causes what three major problems for the host:

Answer 46

(1) inflammation of the skin, (2) bile duct inflammation in the liver, and (3) damage to intestinal tract.

Question 47

So what are common symptoms of GVHD?

Answer 47

maculopapular skin rash, high serum levels of bilirubin (normal= 0.3-1.9), and diarrhea.

Question 48

Why is it important that most patients receive immunosuppressive drug treatment to prevent the graft from being destroyed by the immune system of the recipient?

Answer 48

Because it is not unusual for transplanted tissue to have at least one mis-matched MHC class I or class II loci

Question 49

What three kinds of drugs are usually given during transplant?

Answer 49

corticosteroids, cytotoxic drugs, and microbial products.

Question 50

A patient with no surgical history that has type O+ blood receives a kidney transplant with mismatches at HLA-A and HLA-DR from a donor with AB- blood. How long will the transplant survive if no immunosuppressive drugs are given?

Answer 50

24-72 hrs immunosuppressants would not change the result

Question 51

A patient with type B+ blood (RhD+) could safely receive multiple infusions with which blood types?

Answer 51

Type B+, B-, O+, or O-

Question 52

Which blood type is the universal recipient?

Answer 52

Type AB

Question 53

A patient with type A blood mistakenly receives a transfusion with AB donor blood. Which of the following symptoms/clinical findings would not occur 24 hours in the patient without intervention?a) arthralgiab) Decrease in kidney functionc) Increase in serum C1qd) Increase in serum C5a levelse) Neurological dysfunction

Answer 53

C. This is essentially a type II hypersensitivity disease Deposition of immune complex will cause the other symptoms for a,b,d, and e

Question 54

A patient that rejected a kidney (mismatches at HLA-A and B) two years ago receives a second kidney transplant (mismatched at HLA-B). In the absence of immunosuppressive drug, how long will the graft be expected to survive?

Answer 54

5-8 days. Very quick because preformed CTLs will be formed this is second set rejection

Question 55

Although an unlikely scenario, a patient with which inherited immunodeficiencies would be able to successful receive a blood group matched allogeneic kidney transplant without the need for anti-inflammatory therapy?a) adenosine deaminase deficiencyb) Bruton’s tyrosine kinase deficiencyc) CD-40 ligand deficiencyd) Chediak-Higashi syndromee) Cytidine deaminase deficiencyf) IFN-y receptor deficiencyg) MPO deficiencyh) Neutropenia

Answer 55

a) Adenosine deaminase deficiency

Question 56

A patient with type A blood could safely receive a transfusion form a patient with?

Answer 56

Type A and O

Question 57

A 53 y/o received a liver transplant an received appropriate anti-inflammatory drug treatment. On day 36 post op, she presented with abdominal pain with diarrhea that worsened over the next several days. She also presented with sever skin rashes covering a large percentage of her body. What was occurring?a) acute rejectionb) chronic rejectionc) graft vs. host diseased) hyperacute rejectione) autoimmune condition unrelated to the transplant

Answer 57

Graft vs. host disease (more likely in liver)

Question 58

An Rhd+ woman is known to be carrying a Rhd- fetus. When should RhoGAM be administered?

Answer 58

Never, RhoGAM is not indicated

Question 59

A patient with which of the following inherited immunodeficiencies would be most likely to reject a kidney transplant that has mismatches at HLA-A and B?

Answer 59

DiGeorge syndrome

Question 60

Your patient is type O. Which blood type antibodies are in her circulation?

Answer 60

Anti-A and Anti-B

Question 61

Your patient that received a corneal transplant three months earlier comes in with severe eye inflammation. What is your best guess as to what is causing the inflammatory response?

Answer 61

Microbial infection. Cornea is avascular

Question 62

A patient with no surgical history that has type A- blood receives a kidney transplant with a perfect MHC haplotype from a donor with Type O- blood. no immunosuppressive drugs were given. Despite the perfect MHC haplotype match, the kidney was rejected. How long did it take for this graft to be rejected?

Answer 62

30-60 days

Question 63

A patient with no surgical history that has type B+ blood receives a kidney transplant with mismatches at HLA-A and HLA-DR from a donor with type O- blood. How long will the transplant survive if no immunosuppressive drugs are given?

Answer 63

10-15 days first-set rejection

Question 64

A 22-year-old primigravid woman at 28 weeks gestation comes in for her regular prenatal check-up. After discussing her diet, exercise regimen and lifestyle, as well as reviewing her laboratory test results, her physician administers an injection of anti-RhD immunoglobulin. The anti-RhD is a preparation of which antibody isotype?

Answer 64

The correct answer choice is “IgG”. This is a definitional question. Anti-RhD (RhoGAM) is an IgG product. I can’t think of any way to extend this question rationale. Well, here is one way. I have had numerous questions about whether these anti-RhD antibodies can cross the placental barrier and bind to the fetal RBCs. The answer is that they can, because all IgG can cross the placenta. However, they will not cause a problem in the fetus because the antibodies are not at a high enough concentration to cause destruction of significant numbers of fetal RBCs. Many copies of the antibody would have to bind to any specific RBC to mediate complement-mediated lysis (via MAC). Since all of the RBCs express RhD, the antibodies are simply too dilute to cause a problem. In contrast, if fetal RBCs get into the mother’s circulation (for whatever reason), there are relatively few fetal RBCs, so the concentration of antibodies is sufficient to result in many copies binding to each fetal RBC, allowing lots of MAC formation and destruction of the RBCs.

Question 65

A 38-year-old female that had been on the transplant list for 2 years after suffering a massive heart attack that caused myocardial damage finally receives a heart transplant from a well-matched donor. Three weeks later, she begins to suffer dyspnea upon exertion. A clinical evaluation including a biopsy is performed. Which of the following clinical findings would be most consistent with acute graft rejection?

Answer 65

The correct answer choice is “Dense interstitial lymphocytic infiltrate”. Acute graft rejection is mediated by CTLs that have specificity for alloantigens of the grafted tissue. During acute graft rejection, interstitial infiltration of CTLs would be evident on the biopsy. Three of the answer choices (Antibodies bound to the vascular endothelial cells, C3b deposited abundantly on the tissues, and interstitial infiltration of abundant NK cells) are dependent on antibodies, but antibodies do not participate in acute graft rejection. TH1 cells and macrophages do not play a significant role in acute rejection either.

Question 66

During a kidney transplant procedure, the surgeon notices that the grafted tissue becomes mottled with a bluish/purple discoloration soon after he connects the recipient’s vessels to the grafted kidney. The blood flow to the graft eventually ceases entirely, and urine output is markedly reduced. Which of the following best explains the condition of the grafted kidney?

Answer 66

The correct answer choice is “Antibody-mediated hypersensitivity”. This is a case of hyperacute graft rejection that occurs following transplantation of tissue into a patient that has a blood group incompatibility with the donor. Antibodies specific for blood group antigen- A and/or B in the recipient’s circulation bind to their determinants on the vascular endothelial cells of the grated tissue, resulting in an inflammatory response that causes occlusion of small vessels. The result is very rapid killing of the grafted tissue. Cell-mediated graft rejection takes much longer to reject transplanted tissue. Graft vs. host disease does not develop this quickly and the immune responses are directed at the recipient’s tissues, not the grafted tissue. Immediate-type hypersensitivity is IgE mediated, and the response that causes hyperacute transplant rejection is mediated primarily by IgM antibodies. Immune complex mediated damage does not occur as a consequence of allogeneic solid organ transplantation.

Question 67

A woman with type B-negative blood gives birth to a baby with type A-negative blood. As expected, the mother has a high titer of anti-A antibodies in her circulation. Significant hemolysis of the baby’s RBCs did not occur in utero because the mother’s anti-A antibodies were predominantly of which class?

Answer 67

The correct answer choice is “IgM”. The anti-A blood group-specific antibodies made by this pregnant woman are produced in response to normal flora bacteria that have very similar structures on their surface. These surface antigens (as well as blood group antigens) are carbohydrate structures, and as such are T-independent antigens. Therefore, the vast majority of blood group A-specific antibodies are of the IgM isotype and are unable to cross the placental barrier.

Question 68

A 22-year-old female was brought to the ER with considerable trauma resulting from an automobile accident. A blood transfusion is administered after abdominal ultrasound reveals a ruptured spleen, and the patient is taken to the operating room for surgery. During transport, the patient begins to suffer breathing difficulty, chills, and pain in the chest and back. Her blood pressure is mildly reduced and stable. Dark-colored urine is observed draining from the urinary catheter. Which of the following is most likely responsible for the new symptoms experienced by this patient?

Answer 68

The correct answer choice is “Complement-mediated cell lysis”. This is a standard presentation of a mismatched blood transfusion, resulting in a transfusion reaction. Blood group-specific antibodies in the recipient’s circulation bound to the transfused RBCs, initiating the complement cascade, resulting in large amounts of C3b deposition and membrane attack complex formation on RBCs, mediating their destruction. The anaphylatoxins produced by the complement cascade as well as the massive amounts of immune complex formation that results initiates acute inflammation that can lead to occlusion of small blood vessels, which can be very damaging to critical organs. Acute tubular injury occurs in the kidney as well. CD8 T cell have no role in this inflammatory response. An endotoxin-induced cytokine storm would be very unlikely in this case because the patient would have had to have an acute septic infection at the time of the traffic accident to present with these symptoms this soon after the accident; moreover, dark-colored urine is not indicative of septic shock. Systemic degranulation of mast cells would result in anaphylactic shock. This patient’s symptoms are not consistent with anaphylaxis because her blood pressure is remaining stable and there is no mention of hives on her skin or vomiting.

Question 69

A 51-year-old male that had received a heart transplant one week earlier develops a widespread scaly skin rash, elevated bilirubin levels, and bloody diarrhea. Imaging studies reveal multiple lesions of the intestinal mucosa. Which of the following are most likely to be the cause of the patient’s current condition?

Answer 69

The correct answer choice is “B: Graft-derived T cell sensitization against host MHC antigens”. This is a case of graft-vs. host disease that sometimes occurs following bone marrow transplants, and at a much lower frequency occurs following solid organ transplant. This condition is caused by mature naïve T cells from the grafted tissue that enter secondary lymphoid tissues of the recipient and become activated. The T cells typically have specificity for a peptide derived from allogeneic MHC molecules that are expressed by the recipient. Because the donor’s T cell underwent negative selection in the donor’s thymus, the allogeneic MHC determinants produced by the recipient were not available during negative thymic selection in the donor. Mature T cells from the grafted tissue can enter secondary lymphoid tissues and become activated like any other T cell in the repertoire. Once activated, fully differentiated T effector T cells can mediate autoimmune inflammatory responses that damage the recipients tissues. The most commonly affected tissues are the skin, the GI tract, and the liver. Preformed antibody responses have no role in graft-versus-host disease, and host-derived B cells and tissues should be tolerant of host determinants (in most cases). There is no reason that a transplantation procedure would cause an increased in likelihood of autoimmune development mediated by the recipient’s lymphocytes.

Question 70

A 26-year-old woman receives a non-T lymphocyte-depleted, allogeneic bone marrow transplant from a matched, unrelated donor. Immunosuppressive therapy with cyclosporine is started. One month later, she presents with fever and cytolytic destruction of the liver (hepatitis), GI tract (enteritis), and skin (dermatitis). Which of the following best explains these findings?

Answer 70

The correct answer choice is “Graft-versus-host disease”. This is a classic presentation of GVHD. Mature naïve T cells that are infused along with the donor bone morrow can enter secondary lymphoid tissues of the host and sample MHC:peptide complexes presented via APCs. Because there donor T cells underwent negative selection in the donor’s thymus, but not the recipient, it is possible that the cognate determinant of recognized by these T cells could be a peptide derived from the recipient’s allogeneic MHC molecules. It is possible for these T cells to become activated and to proliferate and differentiate into effector CTLs that can now attack any host cell bearing their cognate determinant. The tissues most often targeted are the GI tract, the liver, and the skin.

Question 71

A 28-year-old primigravida (woman having 1st pregnancy) that received no prenatal care gave birth to a child that had a hemoglobin level of 6 g/dL (normal: 12-18 g/dL), many nucleated RBCs (erythroblasts), hepatomegaly, and generalized edema. The infant died soon after birth. Which of the following was the most likely cause of the infant’s condition at birth?

Answer 71

The correct answer choice is “Maternal antibody-mediated RBC lysis”. This is a typical presentation of hemolytic disease of the newborn that results from an Rh incompatibility. The mother was likely RhD-negative and the fetus was Rh-positive. Because this was the mother’s 1st pregnancy (primigravida), she had to have been exposed to the child’s RBCs during the pregnancy. She produced an RhD-specific IgG response and those antibodies crossed the placental barrier and caused widespread destruction of fetal RBCs. The destruction of RBCs leaves the fetus severely anemic, possibly resulting in heart failure. Although it is possible that this child as inherited a deficiency that would result in production of multisystem autoimmunity (e.g. AIRE deficiency, Treg deficiency, Omenn syndrome), it would take several months before the child would be able to prime these responses. Glucose-6-phosphate dehydrogenase deficiency results in anemia, but the anemia would be much less acute that what was seen in the patient, and in fact likely would be subclinical. Infants do not many antibodies until after being born because they are in an essentially sterile environment and are typically not challenges with any non-self materials until the birthing process. Moreover, the child will typically be tolerant of all antigens expressed by its own RBCs and should never mount an antibody response that would have specificity for its own erythrocytes. RhoGAM is an IgG product that will cross the placental barrier after infusion into the mother, but the concentration is too low to cause significant destruction of fetal RBCs (not enough antibody copies per RBC).

Question 72

Your 50-year-old patient that received a kidney transplant 4 years earlier was diagnosed with arterial hypertension 3 months ago, and his current creatinine level is 2.8 mg/dl. Urinalysis is unremarkable, but ultrasonography reveals that the grafted kidney is reduced in size. Which of the following is most likely responsible for the condition of the grafted kidney?

Answer 72

The correct answer choice is “Antibodies specific for alloantigens expressed by cells of the grafted tissue”. This is an example of chronic transplant rejection that can occur from months to years after tissue is transplanted into a recipient. Chronic rejection is not as clearly characterized as acute or hyperacute rejection, and it is likely that T cells can also play a role in the rejection. Chronic rejection of a kidney causes fibrosis (scarring) of the kidney, causing progressive reduction of function. There appears to be controversy over whether antibodies or T cells are the key effectors of chronic rejection. The reason I included this question with this answer it that I saw a similar questions in a step 1 review questions set that suggested that chronic rejection is antibody mediated. I am certain that antibodies can mediate chronic rejection, but I think T cells can also do this in the absence of antibody responses. Certainly, the antibodies would not have specificity for blood group antigens, because if they did, hyperacute rejection of the tissue would have been the result. Phagocytes play no important effector role in transplant rejection. I will not ask about this on the exam, but I think it is important that you are aware that this type of question could be asked on the step 1 exam.

Question 73

A 42-year-old male that had received a kidney transplant two-weeks earlier began to experience low-grade fever and decreased urine output. A biopsy of the grafted tissue reveals dense interstitial mononuclear cell infiltration. Which of the following is the most likely cause of this patient’s current condition?

Answer 73

The correct answer choice is “Host T cell sensitization against graft MHC antigens”. The reduced function of the grafted tissue indicates that the graft is being rejected, and the time frame indicates that acute rejection is occurring. Acute transplant rejection is mediated by T cells (primarily CTLs) that have specificity for alloantigens of the grafted tissue. It is possible for B cells from the grafted tissue could be activated in the recipient, and if B cell(s) have specificity for host determinants, autoimmune disease could develop; however, it would be unlikely for donor B cells to mediate an response that damages the grafted tissue (because the donor should be tolerant of his/her own tissue). If T cells that came in with the graft became activated, it is possible that the recipient could develop graft vs. host disease (if the T cells have specificity for alloantigens of the recipient), but that response would not affect the grafted tissue because the recipient’s T cells should be tolerant to his/her one tissues. Host B cell responses directed at the grafted tissue could result in chronic rejection, but would not play a role in acute graft rejections. If the recipient had preformed antibody responses directed at incompatible ABO antigens of the donor tissue, hyperacute graft rejection (24-48 hours) would have occurred.