USMLE Step 1 Immunology Practice Questions

A ValueMD community study resource: original practice questions covering the core immunology concepts tested on USMLE Step 1.

Immunology questions on Step 1 tend to reward pattern recognition over memorization: knowing which hypersensitivity type a clinical scenario represents, which complement component does what, or which immunoglobulin class fits a given clue. The 45 questions below are organized by topic so you can drill a specific weak area or work through the full set in order.

Educational note: these are original practice questions written for exam review, not a substitute for your course material or a clinical reference.

Hypersensitivity Reactions

1. A child is stung by a bee and within minutes develops facial swelling, wheezing, and hypotension. Which immune mechanism is responsible?

A. IgG-mediated cytotoxicity
B. IgE cross-linking on mast cells
C. Immune complex deposition
D. Sensitized T cell activation

Answer: B. Cross-linking of mast cell-bound IgE by antigen triggers immediate degranulation and the release of histamine and other mediators, producing the immediate (type I) hypersensitivity reaction seen in anaphylaxis.

2. A patient develops fever, joint pain, and a rash 10 days after starting a new antibiotic, along with low complement levels and elevated BUN. Which hypersensitivity mechanism best explains this presentation?

A. Type I, IgE-mediated
B. Type II, cytotoxic
C. Type III, immune complex
D. Type IV, delayed

Answer: C. Serum sickness is the classic example of type III hypersensitivity, in which antigen-antibody complexes deposit in tissues (joints, skin, kidney) and activate complement, consuming it and producing this multi-organ pattern roughly one to two weeks after exposure.

3. A patient treated with methyldopa develops a positive direct Coombs test and hemolytic anemia. Which hypersensitivity type is this?

A. Type I
B. Type II
C. Type III
D. Type IV

Answer: B. Methyldopa-induced hemolytic anemia is a classic type II (cytotoxic) hypersensitivity reaction, in which antibody binds directly to an antigen on the red cell surface, leading to complement- or macrophage-mediated destruction.

4. A positive PPD skin test read 48 to 72 hours after placement reflects which type of hypersensitivity?

A. Type I
B. Type II
C. Type III
D. Type IV

Answer: D. The tuberculin reaction is a delayed-type (type IV) hypersensitivity response, mediated by sensitized helper T cells and macrophages rather than antibody, which is why it takes 48 to 72 hours to develop rather than minutes.

5. Poison ivy contact dermatitis is mediated by which mechanism?

A. IgE bound to mast cells
B. Preformed circulating antibody
C. Sensitized T cells reacting to a hapten-modified antigen
D. Immune complex deposition in the skin

Answer: C. Urushiol acts as a hapten that binds skin proteins, and the resulting hapten-carrier complex is recognized by sensitized T cells, producing a classic type IV cell-mediated reaction.

Complement System

6. A patient with recurrent Neisseria infections is found to have a deficiency in a late complement component. Which component is most likely deficient?

A. C1
B. C3
C. C5 through C9
D. Factor B

Answer: C. The C5-C9 components form the membrane attack complex, which is especially important for defense against Neisseria species. Deficiencies here classically present with recurrent Neisserial infections while leaving other defenses largely intact.

7. Which complement component, when deficient, is most associated with an increased risk of severe recurrent pyogenic bacterial infections and lupus-like immune complex disease?

A. C3
B. C5
C. C9
D. Factor D

Answer: A. C3 sits at the convergence point of both the classical and alternative pathways, so its deficiency severely impairs opsonization and immune complex clearance, producing both recurrent bacterial infections and an SLE-like syndrome.

8. A deficiency of C1 esterase inhibitor produces which clinical condition?

A. Paroxysmal nocturnal hemoglobinuria
B. Hereditary angioedema
C. Chronic granulomatous disease
D. X-linked agammaglobulinemia

Answer: B. C1 esterase inhibitor normally restrains the classical complement pathway and the kinin system. Its deficiency allows unchecked activation, leading to episodes of angioedema without urticaria.

9. Which statement about the alternative complement pathway is correct?

A. It requires antigen-antibody complexes to initiate.
B. It can be triggered directly by microbial surfaces without antibody.
C. It bypasses C3 entirely.
D. It shares no components with the classical pathway.

Answer: B. The alternative pathway is part of innate immunity and can be activated directly by pathogen surfaces (via C3 spontaneous hydrolysis and factor B/D), without requiring a prior antibody response, unlike the classical pathway.

10. C3a and C5a produced during complement activation primarily function as:

A. Opsonins that coat bacteria for phagocytosis
B. Anaphylatoxins that increase vascular permeability and recruit inflammatory cells
C. Membrane attack complex precursors
D. Inhibitors of mast cell degranulation

Answer: B. C3a and C5a are anaphylatoxins: they trigger mast cell degranulation, increase vascular permeability, and act as chemotactic signals that recruit neutrophils to the site of complement activation.

Major Histocompatibility Complex

11. Class I MHC molecules present antigen to which cell type?

A. CD4-positive helper T cells
B. CD8-positive cytotoxic T cells
C. B lymphocytes
D. Natural killer cells exclusively

Answer: B. Class I MHC molecules, expressed on nearly all nucleated cells, present endogenously processed peptides (such as viral proteins) to CD8-positive cytotoxic T cells, which recognize infected or abnormal cells for destruction.

12. Which cell types constitutively express class II MHC molecules?

A. All nucleated cells
B. Only hepatocytes
C. Professional antigen-presenting cells: macrophages, dendritic cells, and B cells
D. Red blood cells

Answer: C. Class II MHC is restricted mainly to professional antigen-presenting cells, which use it to display exogenously processed antigen to CD4-positive helper T cells, initiating the adaptive immune response.

13. A patient receives a kidney from an HLA-identical sibling but still requires immunosuppression. Why?

A. Because class I and class II MHC cannot both be matched simultaneously
B. Because minor histocompatibility antigens remain mismatched
C. Because complement proteins are always rejected
D. Because ABO blood group is unrelated to MHC matching

Answer: B. Even with full HLA matching, differences in minor histocompatibility antigens (unrelated to the MHC genes themselves) can still trigger a graft rejection response, so immunosuppression is still required.

14. Grafts exchanged between identical twins are unique in that they:

A. Are rejected slowly due to minor antigen mismatch
B. Undergo hyperacute rejection
C. Are not rejected even without immunosuppression
D. Require lifelong immunosuppression regardless of genetic identity

Answer: C. Identical twins share both major and minor histocompatibility antigens, so a graft between them is treated as self and is not rejected, even without any immunosuppressive therapy.

15. Which of the following best describes the role of class II MHC in graft rejection?

A. It is recognized by cytotoxic T cells, which directly destroy donor cells.
B. It is recognized by helper T cells, which then activate cytotoxic T cells and B cells against the graft.
C. It has no role in graft rejection, only class I does.
D. It induces IgE-mediated rejection.

Answer: B. Donor class II MHC on graft cells is recognized by recipient helper T cells, which then orchestrate the broader rejection response by activating cytotoxic T cells and antibody production.

Immunoglobulins and B Cell Biology

16. Which immunoglobulin class is present in highest concentration in a healthy newborn’s serum, and why?

A. IgM, produced by the fetus
B. IgG, transferred across the placenta from the mother
C. IgA, from breast milk
D. IgE, from maternal transfer

Answer: B. IgG is the only immunoglobulin class that crosses the placenta, via active FcRn-mediated transport, so a newborn’s serum IgG largely reflects maternal antibody until the infant’s own production ramps up.

17. Which immunoglobulin is most abundant in mucosal secretions such as saliva and breast milk?

A. IgG
B. IgM
C. IgA
D. IgD

Answer: C. Secretory IgA, stabilized by a secretory component, is the dominant immunoglobulin in mucosal secretions and provides localized mucosal immunity, including passive protection for breastfed infants.

18. A patient’s antibody response to a repeat vaccine exposure is faster, of higher titer, and dominated by IgG rather than IgM. This reflects:

A. A primary immune response
B. A secondary (anamnestic) immune response
C. An autoimmune reaction
D. Complement deficiency

Answer: B. Memory B cells generated during the primary response allow a faster, larger, and class-switched (IgG-dominant) secondary response upon re-exposure to the same antigen.

19. Isotype switching in B cells (for example, from IgM to IgG) involves:

A. A change in the variable region, altering antigen specificity
B. A change in the constant region only, preserving antigen specificity
C. Loss of antigen-binding capacity
D. Replacement of light chains only

Answer: B. Isotype switching recombines the heavy-chain constant region genes while preserving the same variable region, so the antibody keeps its original antigen specificity but gains a new effector function associated with the new class.

20. Which immunoglobulin, when bound to mast cells, mediates immediate hypersensitivity reactions upon antigen cross-linking?

A. IgA
B. IgM
C. IgG
D. IgE

Answer: D. IgE binds high-affinity Fc receptors on mast cells and basophils. Cross-linking of this bound IgE by allergen triggers degranulation, producing the immediate hypersensitivity response.

Cell-Mediated Immunity and Cytokines

21. Th1 cells primarily promote which type of immune response through which key cytokine?

A. Antibody-mediated immunity, via IL-4
B. Cell-mediated immunity, via interferon-gamma
C. Eosinophil recruitment, via IL-5
D. Regulatory suppression, via IL-10

Answer: B. Th1 cells secrete interferon-gamma, which activates macrophages and promotes cell-mediated immunity, particularly important in defense against intracellular pathogens.

22. Th2 cells primarily support which arm of the immune response?

A. Cytotoxic T cell-mediated killing
B. Antibody-mediated (humoral) immunity and allergic responses, via IL-4 and IL-5
C. Complement activation
D. Neutrophil-mediated phagocytosis

Answer: B. Th2 cells produce IL-4 and IL-5, which promote B cell antibody production (including IgE class switching) and eosinophil activity, making this subset central to humoral immunity and allergic/parasitic responses.

23. Natural killer cells are distinct from cytotoxic T cells in that they:

A. Require prior antigen sensitization to kill target cells
B. Can kill virus-infected or tumor cells without prior sensitization
C. Only function in the presence of antibody
D. Express CD8 and require MHC class I recognition to kill

Answer: B. Natural killer cells are part of innate immunity and can recognize and kill abnormal cells (such as those lacking MHC class I) without needing prior exposure or sensitization, unlike cytotoxic T cells.

24. A child presents with recurrent severe infections from birth and is found to have a near-total absence of both T and B lymphocytes. This is most consistent with:

A. X-linked agammaglobulinemia
B. DiGeorge syndrome
C. Severe combined immunodeficiency (SCID)
D. Chronic granulomatous disease

Answer: C. SCID results from defects affecting both T and B cell development (several genetic causes exist), producing a profound combined immunodeficiency that presents with severe infections very early in life.

25. A child has recurrent infections with catalase-positive organisms and a nitroblue tetrazolium test result consistent with impaired neutrophil oxidative burst. This is most consistent with:

A. Chronic granulomatous disease
B. Chediak-Higashi syndrome
C. Leukocyte adhesion deficiency
D. Hereditary angioedema

Answer: A. Chronic granulomatous disease results from a defect in the NADPH oxidase complex, impairing the neutrophil oxidative burst needed to kill catalase-positive organisms, and is classically demonstrated by an abnormal nitroblue tetrazolium (or newer flow cytometry-based) test.

Transplant Immunology and Autoimmunity

26. Hyperacute graft rejection occurs within minutes to hours and is caused by:

A. Newly formed cytotoxic T cells against the graft
B. Preformed recipient antibodies against donor antigens
C. Delayed-type hypersensitivity
D. Cytokine storm from Th1 cells

Answer: B. Hyperacute rejection is mediated by preexisting recipient antibodies (for example, from prior transfusions, transplants, or pregnancies) that bind donor antigens immediately upon graft perfusion, activating complement and causing rapid vascular thrombosis.

27. Acute graft rejection, typically occurring weeks to months after transplant, is primarily mediated by:

A. Preformed antibody
B. T cell-mediated immune responses to donor MHC
C. Fibrosis alone
D. Innate immunity exclusively

Answer: B. Acute rejection is primarily a cell-mediated process, driven by recipient T cells recognizing donor MHC antigens, and it’s typically the type of rejection immunosuppressive drug regimens are designed to prevent.

28. Graft-versus-host disease occurs when:

A. Recipient T cells attack donor tissue
B. Immunocompetent donor T cells (as in a bone marrow transplant) attack the recipient’s tissues
C. The recipient rejects the donor kidney
D. Complement destroys the donor organ

Answer: B. Graft-versus-host disease is a particular risk of bone marrow and stem cell transplantation, where mature donor T cells recognize the recipient’s tissues as foreign and mount an immune attack against them.

29. Systemic lupus erythematosus is most classically associated with antibodies against:

A. Acetylcholine receptor
B. Double-stranded DNA
C. TSH receptor
D. Streptococcal M protein

Answer: B. Anti-double-stranded DNA antibodies are a hallmark of systemic lupus erythematosus and correlate with disease activity, particularly lupus nephritis, more than most other autoantibodies used in diagnosis.

30. Graves’ disease results from autoantibodies that:

A. Destroy thyroid follicular cells
B. Bind and stimulate the TSH receptor
C. Block acetylcholine receptors at the neuromuscular junction
D. Target the glomerular basement membrane

Answer: B. Graves’ disease is caused by stimulating autoantibodies against the TSH receptor, which mimic TSH and drive continuous thyroid hormone overproduction, distinguishing it mechanistically from most other autoimmune conditions that destroy rather than stimulate their target.

Frequently Asked Questions

What’s the fastest way to tell the four hypersensitivity types apart on Step 1? Focus on timing and mediator: type I is immediate and IgE-mediated (minutes), type II is antibody against a fixed cell-surface antigen (as in hemolytic anemia), type III is immune complex deposition causing systemic symptoms roughly one to two weeks after exposure, and type IV is T cell-mediated and delayed (48 to 72 hours), with no antibody involved at all.

Why do complement deficiencies cause different symptoms depending on which component is missing? Early components (C1, C2, C4) mainly affect immune complex clearance and are linked to lupus-like disease, C3 deficiency causes severe recurrent bacterial infections since it’s central to opsonization, and late component (C5-C9) deficiencies specifically predispose to Neisseria infections since that pathway’s membrane attack complex is especially important against that organism.

What’s the easiest way to remember class I vs. class II MHC? Class I pairs with CD8 (both are single digits in a sense, “1 times 8 equals 8”), presents endogenous antigen, and is found on virtually all nucleated cells. Class II pairs with CD4 (“2 times 4 equals 8” gives the same trick), presents exogenous antigen, and is restricted to professional antigen-presenting cells.

How is graft-versus-host disease different from ordinary graft rejection? In ordinary rejection, the recipient’s immune system attacks the transplanted organ. In graft-versus-host disease, it’s reversed: immunocompetent donor T cells (present in a bone marrow or stem cell graft) attack the recipient’s own tissues, which is why it’s a unique risk of transplants that carry live donor immune cells rather than solid organs.

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