USMLE practice question #133 will test your understanding of the mechanism behind a commonly tested immunology condition.
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A 50-year-old man underwent an allogeneic hematopoietic stem cell transplant for treatment of acute myeloid leukemia. Three weeks after the transplant, he develops a maculopapular rash on his trunk and extremities, diarrhea, and elevated liver enzymes. A skin biopsy reveals lymphocytic infiltration and apoptosis of epidermal keratinocytes. Which of the following best describes the mechanism responsible for his symptoms?
A) Activation of host dendritic cells by donor-derived antigens
B) Recognition of host antigens by donor T cells
C) Loss of self-tolerance in the host immune system
D) Complement-mediated lysis of donor cells by preformed host antibodies
E) Bystander activation of host macrophages by donor cytokines
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best describes the mechanism responsible for his symptoms?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Diagnose the problem; 2nd: Identify the underlying mechanism.
Step 3: Read the vignette carefully and ask yourself: “Based on this patient’s presentation and history, the underlying cause is most likely ______________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 50-year-old man presents with acute graft-versus-host disease (aGVHD) following an allogeneic hematopoietic stem cell transplant. He has developed a maculopapular rash, diarrhea, and elevated liver enzymes three weeks after the transplant. These symptoms, along with the skin biopsy showing lymphocytic infiltration and keratinocyte apoptosis, are classic for aGVHD.
ANSWER CHOICES:
CHOICE A: Activation of host dendritic cells by donor-derived antigens
Explanation: Host dendritic cells can present donor antigens in certain transplant rejection scenarios, such as host-versus-graft responses. In graft-versus-host disease, it is the donor T cells that recognize and attack host antigens, not the host immune system responding to donor antigens.
CHOICE B: Recognition of host antigens by donor T cells
Explanation: In aGVHD, donor T cells recognize host antigens (such as major or minor histocompatibility antigens) as foreign. This triggers an immune response where donor T cells infiltrate target tissues (e.g., skin, liver, GI tract) and mediate tissue damage via cytotoxic mechanisms (e.g., perforin/granzyme pathway, Fas/FasL pathway).
CHOICE C: Loss of self-tolerance in the host immune system
Explanation: Loss of self-tolerance is characteristic of autoimmune diseases, where the host's immune system attacks its own tissues. GVHD is caused by donor immune cells attacking host tissues, not by a failure of the host immune system to maintain self-tolerance.
CHOICE D: Complement-mediated lysis of donor cells by preformed host antibodies
Explanation: This describes hyperacute rejection in solid organ transplantation, where preformed host antibodies target donor antigens and activate complement, leading to rapid graft destruction. GVHD involves donor T cells attacking recipient tissues; complement-mediated lysis is not involved.
CHOICE E: Bystander activation of host macrophages by donor cytokines
Explanation: Macrophages can be activated during inflammatory responses but are not the primary mediators of GVHD. The primary mechanism in GVHD is direct recognition of host antigens by donor T cells, not bystander activation of macrophages.
FINAL VERDICT…
CORRECT ANSWER: B) Recognition of host antigens by donor T cells
In acute graft-versus-host disease, donor T cells recognize the recipient's antigens as foreign and mount an immune response against the recipient's tissues. This process leads to inflammation and tissue damage in target organs such as the skin, liver, and gastrointestinal tract.
KEY CONCEPTS:
Pathophysiology of Acute GVHD:
Donor T cells recognize recipient major or minor histocompatibility antigens as foreign.
Activation of donor T cells leads to cytokine release (e.g., TNF-α, IFN-γ) and recruitment of cytotoxic lymphocytes.
Tissue damage occurs via cytotoxic pathways (e.g., perforin/granzyme or Fas/FasL).
Clinical Features of Acute GVHD:
Skin: Maculopapular rash that may progress to blistering or desquamation.
GI tract: Diarrhea, abdominal pain, nausea/vomiting.
Liver: Elevated liver enzymes (ALT/AST), bilirubin elevation, jaundice.
Histological Findings in Acute GVHD:
Lymphocytic infiltration.
Apoptosis of keratinocytes in the skin.
Crypt cell apoptosis in the GI tract.
Hepatocyte apoptosis in the liver.
Risk Factors for GVHD:
HLA mismatch between donor and recipient.
Reduced-intensity conditioning regimens.
Older age or comorbidities in recipient.
Management of Acute GVHD:
Immunosuppressive therapy (e.g., corticosteroids).
Prophylaxis with calcineurin inhibitors (e.g., cyclosporine or tacrolimus).