Immunology for USMLE Step 1

A 9-month-old boy has had recurrent otitis media, pneumonia and sinusitis with encapsulated organisms since around 6 months of age. Serum immunoglobulins of all classes are markedly reduced. Flow cytometry shows absent circulating B cells with normal T cell numbers. Tonsils are absent on examination. What is the underlying defect?

1. Deficiency of terminal complement components C5 to C9 Wrong. Missing the late complement proteins (C5 to C9) specifically causes repeated Neisseria infections, with normal antibody levels and normal B cells.
2. A mutation in Bruton tyrosine kinase preventing B cell maturation correct Correct. This is X-linked agammaglobulinemia. A mutation in Bruton tyrosine kinase (BTK) stops B cells from developing past an early stage (the pre-B stage), so the body has no mature B cells, no antibodies (immunoglobulin) of any class, and no lymphoid tissue like tonsils. Symptoms start around six months of age, once the antibodies the baby got from the mother (maternal IgG) run out.
3. Defective class switching due to a CD40 ligand mutation Wrong. A CD40 ligand mutation causes hyper-IgM syndrome, in which IgM is normal or HIGH while the other antibody classes are low. The key difference is that B cells are still present in hyper-IgM syndrome, but this child has none.
4. Failure of NADPH oxidase in phagocytes Wrong. Failure of NADPH oxidase in phagocytes causes chronic granulomatous disease, with infections from catalase-positive organisms and clumps of inflammatory tissue (granulomas). Antibody levels are normal in this condition.
5. A defect in the common gamma chain of cytokine receptors Wrong. A defect in the common gamma chain of cytokine receptors causes severe combined immunodeficiency (SCID), which shows up earlier and is much more severe, with no T cells, opportunistic infections, and failure to thrive.

The point: Symptoms starting around 6 months as the mother's IgG antibodies fall off, infections from encapsulated bacteria, no B cells, and no tonsils all point to X-linked agammaglobulinemia. Compare this with common variable immunodeficiency, which shows up in the teenage or adult years with normal numbers of B cells but poor antibody production.

Source: USMLE Content Outline — immunology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

Four hours after a blood transfusion a patient develops fever, hypotension, flank pain and hemoglobinuria. Direct antiglobulin test is positive and free hemoglobin is detected in the plasma. Which hypersensitivity mechanism is responsible?

1. Type IV: T cell mediated delayed hypersensitivity Wrong. T cell-mediated delayed hypersensitivity describes contact dermatitis, the tuberculin skin test reaction, and graft rejection. It takes 48 to 72 hours to develop and does not involve antibodies at all.
2. Type II: antibody binding to cell surface antigen with complement activation correct Correct. This is an acute hemolytic transfusion reaction from ABO blood type mismatch. Antibodies (IgM) that were already present in the patient's blood bind to the donor red cells and activate the complement system all the way to the membrane attack complex, destroying the cells INSIDE the blood vessels (intravascular hemolysis) and releasing hemoglobin into the urine.
3. Type III: immune complex deposition Wrong. Immune complex deposition describes serum sickness and post-streptococcal glomerulonephritis. These complexes settle in blood vessel walls over days, they do not destroy transfused red cells within hours like this.
4. Type I: IgE-mediated mast cell degranulation Wrong. IgE-mediated mast cell activity describes an anaphylactic transfusion reaction, classically seen in patients who are missing IgA and have made antibodies against it (anti-IgA). It causes hives (urticaria), airway tightening (bronchospasm), and shock, WITHOUT hemolysis.
5. Non-immune osmotic lysis Wrong. Non-immune osmotic lysis would happen if the blood cells were mixed with a fluid that has too little salt (hypotonic fluid), and it would not cause fever, flank pain, or a positive direct antiglobulin test like this case shows.

The point: Sort transfusion reactions by timing: anaphylactic reactions happen within minutes and are linked to IgA deficiency. Acute hemolytic reactions happen within an hour, from ABO mismatch, a type II reaction. Febrile non-hemolytic reactions happen 1 to 6 hours later, from cytokines released by donor white blood cells. TRALI (transfusion-related acute lung injury) happens within 6 hours, from donor anti-HLA antibodies. Delayed hemolytic reactions happen days later, from the immune system remembering a past exposure (an anamnestic response).

Source: USMLE Content Outline — immunology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A 5-year-old boy has had recurrent Staphylococcus aureus and Aspergillus infections with lymphadenitis and liver abscesses. Dihydrorhodamine flow cytometry shows failure of fluorescence on stimulation. Which defect does this identify?

1. Absent Bruton tyrosine kinase Wrong. Missing Bruton tyrosine kinase describes X-linked agammaglobulinemia, with no B cells and no antibodies, infections from encapsulated bacteria and enteroviruses, and a normal oxidative burst.
2. Terminal complement (C5 to C9) deficiency Wrong. Missing the late complement proteins (C5 to C9) causes repeated Neisseria infections specifically, with a normal phagocyte oxidative burst.
3. NADPH oxidase deficiency in phagocytes correct Correct. This is chronic granulomatous disease. Without the burst of reactive oxygen (respiratory burst) that phagocyte cells normally use, they can still swallow (engulf) bacteria but cannot kill them. Catalase-POSITIVE organisms, which can destroy their own hydrogen peroxide, survive inside the cell. The dihydrorhodamine test has replaced the older nitroblue tetrazolium test as the preferred way to diagnose this.
4. Defective microtubule polymerisation in phagosome-lysosome fusion Wrong. A defect in microtubule assembly needed for phagosome-lysosome fusion describes Chédiak–Higashi syndrome, with giant granules inside cells, partial albinism, and nerve damage (peripheral neuropathy).
5. Defective leukocyte integrin CD18 Wrong. A defect in the leukocyte integrin CD18 causes leukocyte adhesion deficiency, with delayed umbilical cord separation, repeated infections WITHOUT pus, and a persistently high neutrophil count.

The point: Catalase-positive organisms to remember in chronic granulomatous disease: Staphylococcus aureus, Serratia, Burkholderia cepacia, Nocardia, Aspergillus, and Candida. Manage the condition with preventive (prophylactic) trimethoprim-sulfamethoxazole, itraconazole, and interferon gamma.

Source: USMLE Content Outline — immunology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator