What is the mechanism of action of Cyclosporine versus Tacrolimus in immunosuppression?

Both are calcineurin inhibitors: Cyclosporine binds cyclophilin, while Tacrolimus binds FKBP-12. Both block calcineurin phosphatase activity, preventing NFAT dephosphorylation and blocking IL-2 transcription.

What defines Type III hypersensitivity reactions, and what are classic prototypical conditions?

Deposition of circulating antigen-antibody immune complexes in vascular beds, activating complement and recruiting neutrophils. Examples: Serum sickness, Systemic Lupus Erythematosus (SLE), and Poststreptococcal glomerulonephritis (PSGN).

What is the immunological mechanism of Type II hypersensitivity, and what are three classic clinical examples?

Antibody (IgG or IgM) directed against fixed cell-surface or tissue antigens, causing complement activation, ADCC, or receptor agonism/antagonism. Examples: Goodpasture syndrome, Myasthenia gravis, and Pemphigus vulgaris.

What is the defect in Hyper-IgM syndrome and what clinical susceptibility pattern does it produce?

Most commonly X-linked mutation in CD40L on activated CD4+ T cells, preventing immunoglobulin class switching in B cells. Marked by normal/elevated IgM, absent IgG/IgA/IgE, and susceptibility to severe opportunistic infections like Pneumocystis jirovecii.

Which major cytokines are secreted by Th1 cells, and what transcription factor regulates Th1 differentiation?

IL-2, IFN-gamma, and TNF-beta (lymphotoxin-alpha); regulated by the transcription factor T-bet. Th1 cells promote cell-mediated immunity and activate macrophages.

What immunological mechanism mediates Type IV (delayed-type) hypersensitivity?

Cell-mediated reaction where sensitized CD4+ (Th1/Th17) or CD8+ T lymphocytes release cytokines upon antigen re-exposure, recruiting macrophages and cytotoxic effectors; peak reaction occurs at 48–72 hours (e.g., PPD tuberculin test, contact dermatitis).

Which HLA class I allele is strongly associated with Ankylosing Spondylitis and reactive arthritis?

HLA-B27 (part of the seronegative spondyloarthropathies: PAIR — Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis).

What is the immunological role of CD28 and CTLA-4 on T cells?

CD28 binds B7-1/B7-2 (CD80/CD86) on antigen-presenting cells to provide the necessary co-stimulatory Signal 2 for T-cell activation. CTLA-4 also binds B7 with higher affinity, delivering an inhibitory signal to terminate T-cell responses.

What is the mechanism of C1 esterase inhibitor deficiency, and what severe clinical risk does it pose?

Hereditary angioedema: unregulated activation of the kallikrein-kinin system causes excessive bradykinin generation, leading to episodic non-pitting mucosal and cutaneous angioedema without pruritus or urticaria; life-threatening laryngeal edema.

What is the role of the TAP (Transporter associated with Antigen Processing) protein in antigen presentation?

Transports proteasome-cleaved endogenous cytosolic peptide fragments into the endoplasmic reticulum lumen, where they are loaded onto newly assembled MHC Class I molecules.

What is the primary immunological defect in Ataxia-Telangiectasia?

Mutation in the ATM gene on chromosome 11q22, disabling double-strand DNA break repair by non-homologous end joining. Causes cerebellar ataxia, oculocutaneous telangiectasias, profound IgA and IgE deficiency, and severe sensitivity to ionizing radiation.

What genetic deletion and embryonic pharyngeal pouch maldevelopment cause DiGeorge syndrome?

22q11.2 microdeletion causing defective development of the 3rd and 4th pharyngeal pouches. Triad: Thymic hypoplasia (T-cell immunodeficiency), Parathyroid hypoplasia (hypocalcemia and tetany), and Conotruncal cardiac defects (Truncus arteriosus, Tetralogy of Fallot).

What is the underlying defect and clinical presentation of Severe Combined Immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency?

ADA deficiency causes toxic accumulation of dATP, inhibiting ribonucleotide reductase and DNA synthesis, which destroys developing T and B lymphocytes, leading to failure to thrive, chronic candidiasis, and recurrent severe infections.

What is the mechanism of action of Sirolimus (Rapamycin) and how does its toxicity profile differ from Tacrolimus?

Binds FKBP-12 to inhibit mTOR (mammalian target of rapamycin), blocking downstream cell cycle progression in response to IL-2. Unlike Tacrolimus and Cyclosporine, Sirolimus is non-nephrotoxic but causes hyperlipidemia and bone marrow suppression (pancytopenia).

What is the function of the invariant chain (Ii / CD74) in MHC class II synthesis?

Binds the antigen-binding peptide groove of MHC class II in the endoplasmic reticulum to prevent premature binding of endogenous peptides, directing MHC class II to the late endosome/lysosome where the CLIP fragment is exchanged for exogenous peptide by HLA-DM.

What is the mechanism and timing of Hyperacute transplant rejection?

Occurs within minutes to hours; preformed host recipient antibodies bind donor endothelial ABO or HLA antigens, triggering immediate complement activation, widespread thrombosis, and graft infarction.

Which HLA class II alleles carry the highest risk for Type 1 Diabetes Mellitus?

HLA-DR3 and HLA-DR4 (specifically DQ8 and DQ2 serotypes).

What genetic defect causes X-linked Agammaglobulinemia (Bruton agammaglobulinemia)?

Mutation in the Bruton tyrosine kinase (BTK) gene, halting pre-B cell maturation into mature B cells. Results in absence of circulating CD19+/CD20+ B cells and profound deficiency of all immunoglobulin classes.

What is the genetic etiology and classic triad of Wiskott-Aldrich syndrome?

X-linked mutation in the WAS gene causing defective actin cytoskeleton remodeling in leukocytes and platelets. Triad: Thrombocytopenia with small platelets (microthrombocytes), Eczema, and Recurrent pyogenic/opportunistic infections.

What is Graft-versus-Host Disease (GVHD), and what organs are predominantly targeted?

Graft immunocompetent donor T cells react against host recipient HLA alloantigens in an immunocompromised host (allogeneic bone marrow transplant). Classic target organs: skin (maculopapular rash, desquamation), gastrointestinal tract (bloody diarrhea), and liver (hyperbilirubinemia, jaundice).

What is the immunological mechanism of Type I (immediate) hypersensitivity reactions?

Antigen cross-links preformed specific IgE antibodies bound to high-affinity Fc-epsilon-RI receptors on mast cells and basophils, triggering immediate degranulation of histamine, tryptase, and leukotrienes.

What clinical syndrome results from a congenital mutation in the FOXP3 gene?

IPEX syndrome: Immune dysregulation, Polyendocrinopathy (type 1 diabetes, thyroiditis), Enteropathy (severe intractable secretory diarrhea), and X-linked inheritance, caused by absent functional Tregs.

What cell surface markers are found on natural killer (NK) cells, and what triggers their cytotoxic activity?

CD16 (Fc-gamma-RIII) and CD56. They kill target cells lacking MHC class I ('missing self') or via antibody-dependent cellular cytotoxicity (ADCC) through CD16 binding the Fc portion of IgG.

What is the immunological defect and diagnostic testing in Chronic Granulomatous Disease (CGD)?

Deficiency of NADPH oxidase subunits (usually X-linked gp91phox), preventing generation of superoxide radicals (respiratory burst). Diagnosed via abnormal Dihydrorhodamine (DHR) flow cytometry or negative nitroblue tetrazolium (NBT) test.

What cell surface marker characterizes all mature T lymphocytes, and what markers distinguish helper from cytotoxic T cells?

CD3 is present on all mature T cells as part of the T cell receptor (TCR) complex. Helper T cells express CD4 (binds MHC class II); cytotoxic T cells express CD8 (binds MHC class I).

What is the function of the AIRE (Autoimmune Regulator) gene, and what disease results from its loss-of-function mutation?

Promotes expression of peripheral tissue-restricted self-antigens in the medullary thymic epithelial cells for negative selection of T cells. Mutation causes Autoimmune Polyglandular Syndrome Type 1 (APS-1 / APECED: candidiasis, hypoparathyroidism, adrenal insufficiency).

Which key cytokines are produced by Th2 cells, and what are their specific physiological roles?

IL-4 (induces IgE class switching), IL-5 (eosinophil activation and growth, IgA switching), and IL-13 (mucus production and alternative macrophage activation); driven by GATA-3.

What is the pathophysiologic hallmark of Chronic transplant rejection?

Occurs months to years post-transplant; combination of cell-mediated and humoral responses causing vascular smooth muscle proliferation, intimal thickening, and parenchymal fibrosis/atrophy (e.g., bronchiolitis obliterans in lung, accelerated graft arteriosclerosis in heart).

Patients with Chronic Granulomatous Disease are predominantly vulnerable to which specific class of organisms?

Catalase-positive organisms, including Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus, because these degrade the host's endogenous microbial hydrogen peroxide.

What clinical syndrome results from terminal complement deficiencies (C5 through C9 / MAC)?

Recurrent invasive infections with Neisseria meningitidis and Neisseria gonorrhoeae, due to inability to assemble the membrane attack complex (MAC) and lyse bacterial membranes.

What transcription factor is required for the development of regulatory T cells (Tregs), and what surface markers do they express?

FOXP3. Tregs express CD4 and CD25 (high-affinity IL-2 receptor alpha chain) and secrete anti-inflammatory cytokines IL-10 and TGF-beta.

What distinguishes Acute cellular rejection from Acute humoral (antibody-mediated) rejection in organ transplantation?

Acute cellular rejection is mediated by host T lymphocytes (CD8+ CTLs and CD4+ Th cells) invading graft parenchyma (endothelialitis/tubulitis); acute humoral rejection involves de novo donor-specific antibodies and C4d complement split-product deposition.

USMLE Step 1 — Immunology, Hypersensitivity (I–IV), Immunodeficiencies & Transplant

High-yield immunology: cytokine biology, B and T cell development, HLA associations, Gell and Coombs hypersensitivities, primary immunodeficiencies, and allograft rejection.

Level: basic
Languages: en → en
Cards: 32
Markdown: USMLE Step 1 — Immunology, Hypersensitivity (I–IV), Immunodeficiencies & Transplant (.md)

Flashcards (32)

#	Front (Term / Question)	Back (Definition / Answer)
1	What is the mechanism of action of Cyclosporine versus Tacrolimus in immunosuppression?	Both are calcineurin inhibitors: Cyclosporine binds cyclophilin, while Tacrolimus binds FKBP-12. Both block calcineurin phosphatase activity, preventing NFAT dephosphorylation and blocking IL-2 transcription.
2	What defines Type III hypersensitivity reactions, and what are classic prototypical conditions?	Deposition of circulating antigen-antibody immune complexes in vascular beds, activating complement and recruiting neutrophils. Examples: Serum sickness, Systemic Lupus Erythematosus (SLE), and Poststreptococcal glomerulonephritis (PSGN).
3	What is the immunological mechanism of Type II hypersensitivity, and what are three classic clinical examples?	Antibody (IgG or IgM) directed against fixed cell-surface or tissue antigens, causing complement activation, ADCC, or receptor agonism/antagonism. Examples: Goodpasture syndrome, Myasthenia gravis, and Pemphigus vulgaris.
4	What is the defect in Hyper-IgM syndrome and what clinical susceptibility pattern does it produce?	Most commonly X-linked mutation in CD40L on activated CD4+ T cells, preventing immunoglobulin class switching in B cells. Marked by normal/elevated IgM, absent IgG/IgA/IgE, and susceptibility to severe opportunistic infections like Pneumocystis jirovecii.
5	Which major cytokines are secreted by Th1 cells, and what transcription factor regulates Th1 differentiation?	IL-2, IFN-gamma, and TNF-beta (lymphotoxin-alpha); regulated by the transcription factor T-bet. Th1 cells promote cell-mediated immunity and activate macrophages.
6	What immunological mechanism mediates Type IV (delayed-type) hypersensitivity?	Cell-mediated reaction where sensitized CD4+ (Th1/Th17) or CD8+ T lymphocytes release cytokines upon antigen re-exposure, recruiting macrophages and cytotoxic effectors; peak reaction occurs at 48–72 hours (e.g., PPD tuberculin test, contact dermatitis).
7	Which HLA class I allele is strongly associated with Ankylosing Spondylitis and reactive arthritis?	HLA-B27 (part of the seronegative spondyloarthropathies: PAIR — Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis).
8	What is the immunological role of CD28 and CTLA-4 on T cells?	CD28 binds B7-1/B7-2 (CD80/CD86) on antigen-presenting cells to provide the necessary co-stimulatory Signal 2 for T-cell activation. CTLA-4 also binds B7 with higher affinity, delivering an inhibitory signal to terminate T-cell responses.
9	What is the mechanism of C1 esterase inhibitor deficiency, and what severe clinical risk does it pose?	Hereditary angioedema: unregulated activation of the kallikrein-kinin system causes excessive bradykinin generation, leading to episodic non-pitting mucosal and cutaneous angioedema without pruritus or urticaria; life-threatening laryngeal edema.
10	What is the role of the TAP (Transporter associated with Antigen Processing) protein in antigen presentation?	Transports proteasome-cleaved endogenous cytosolic peptide fragments into the endoplasmic reticulum lumen, where they are loaded onto newly assembled MHC Class I molecules.
11	What is the primary immunological defect in Ataxia-Telangiectasia?	Mutation in the ATM gene on chromosome 11q22, disabling double-strand DNA break repair by non-homologous end joining. Causes cerebellar ataxia, oculocutaneous telangiectasias, profound IgA and IgE deficiency, and severe sensitivity to ionizing radiation.
12	What genetic deletion and embryonic pharyngeal pouch maldevelopment cause DiGeorge syndrome?	22q11.2 microdeletion causing defective development of the 3rd and 4th pharyngeal pouches. Triad: Thymic hypoplasia (T-cell immunodeficiency), Parathyroid hypoplasia (hypocalcemia and tetany), and Conotruncal cardiac defects (Truncus arteriosus, Tetralogy of Fallot).
13	What is the underlying defect and clinical presentation of Severe Combined Immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency?	ADA deficiency causes toxic accumulation of dATP, inhibiting ribonucleotide reductase and DNA synthesis, which destroys developing T and B lymphocytes, leading to failure to thrive, chronic candidiasis, and recurrent severe infections.
14	What is the mechanism of action of Sirolimus (Rapamycin) and how does its toxicity profile differ from Tacrolimus?	Binds FKBP-12 to inhibit mTOR (mammalian target of rapamycin), blocking downstream cell cycle progression in response to IL-2. Unlike Tacrolimus and Cyclosporine, Sirolimus is non-nephrotoxic but causes hyperlipidemia and bone marrow suppression (pancytopenia).
15	What is the function of the invariant chain (Ii / CD74) in MHC class II synthesis?	Binds the antigen-binding peptide groove of MHC class II in the endoplasmic reticulum to prevent premature binding of endogenous peptides, directing MHC class II to the late endosome/lysosome where the CLIP fragment is exchanged for exogenous peptide by HLA-DM.
16	What is the mechanism and timing of Hyperacute transplant rejection?	Occurs within minutes to hours; preformed host recipient antibodies bind donor endothelial ABO or HLA antigens, triggering immediate complement activation, widespread thrombosis, and graft infarction.
17	Which HLA class II alleles carry the highest risk for Type 1 Diabetes Mellitus?	HLA-DR3 and HLA-DR4 (specifically DQ8 and DQ2 serotypes).
18	What genetic defect causes X-linked Agammaglobulinemia (Bruton agammaglobulinemia)?	Mutation in the Bruton tyrosine kinase (BTK) gene, halting pre-B cell maturation into mature B cells. Results in absence of circulating CD19+/CD20+ B cells and profound deficiency of all immunoglobulin classes.
19	What is the genetic etiology and classic triad of Wiskott-Aldrich syndrome?	X-linked mutation in the WAS gene causing defective actin cytoskeleton remodeling in leukocytes and platelets. Triad: Thrombocytopenia with small platelets (microthrombocytes), Eczema, and Recurrent pyogenic/opportunistic infections.
20	What is Graft-versus-Host Disease (GVHD), and what organs are predominantly targeted?	Graft immunocompetent donor T cells react against host recipient HLA alloantigens in an immunocompromised host (allogeneic bone marrow transplant). Classic target organs: skin (maculopapular rash, desquamation), gastrointestinal tract (bloody diarrhea), and liver (hyperbilirubinemia, jaundice).
21	What is the immunological mechanism of Type I (immediate) hypersensitivity reactions?	Antigen cross-links preformed specific IgE antibodies bound to high-affinity Fc-epsilon-RI receptors on mast cells and basophils, triggering immediate degranulation of histamine, tryptase, and leukotrienes.
22	What clinical syndrome results from a congenital mutation in the FOXP3 gene?	IPEX syndrome: Immune dysregulation, Polyendocrinopathy (type 1 diabetes, thyroiditis), Enteropathy (severe intractable secretory diarrhea), and X-linked inheritance, caused by absent functional Tregs.
23	What cell surface markers are found on natural killer (NK) cells, and what triggers their cytotoxic activity?	CD16 (Fc-gamma-RIII) and CD56. They kill target cells lacking MHC class I ('missing self') or via antibody-dependent cellular cytotoxicity (ADCC) through CD16 binding the Fc portion of IgG.
24	What is the immunological defect and diagnostic testing in Chronic Granulomatous Disease (CGD)?	Deficiency of NADPH oxidase subunits (usually X-linked gp91phox), preventing generation of superoxide radicals (respiratory burst). Diagnosed via abnormal Dihydrorhodamine (DHR) flow cytometry or negative nitroblue tetrazolium (NBT) test.
25	What cell surface marker characterizes all mature T lymphocytes, and what markers distinguish helper from cytotoxic T cells?	CD3 is present on all mature T cells as part of the T cell receptor (TCR) complex. Helper T cells express CD4 (binds MHC class II); cytotoxic T cells express CD8 (binds MHC class I).
26	What is the function of the AIRE (Autoimmune Regulator) gene, and what disease results from its loss-of-function mutation?	Promotes expression of peripheral tissue-restricted self-antigens in the medullary thymic epithelial cells for negative selection of T cells. Mutation causes Autoimmune Polyglandular Syndrome Type 1 (APS-1 / APECED: candidiasis, hypoparathyroidism, adrenal insufficiency).
27	Which key cytokines are produced by Th2 cells, and what are their specific physiological roles?	IL-4 (induces IgE class switching), IL-5 (eosinophil activation and growth, IgA switching), and IL-13 (mucus production and alternative macrophage activation); driven by GATA-3.
28	What is the pathophysiologic hallmark of Chronic transplant rejection?	Occurs months to years post-transplant; combination of cell-mediated and humoral responses causing vascular smooth muscle proliferation, intimal thickening, and parenchymal fibrosis/atrophy (e.g., bronchiolitis obliterans in lung, accelerated graft arteriosclerosis in heart).
29	Patients with Chronic Granulomatous Disease are predominantly vulnerable to which specific class of organisms?	Catalase-positive organisms, including Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus, because these degrade the host's endogenous microbial hydrogen peroxide.
30	What clinical syndrome results from terminal complement deficiencies (C5 through C9 / MAC)?	Recurrent invasive infections with Neisseria meningitidis and Neisseria gonorrhoeae, due to inability to assemble the membrane attack complex (MAC) and lyse bacterial membranes.
31	What transcription factor is required for the development of regulatory T cells (Tregs), and what surface markers do they express?	FOXP3. Tregs express CD4 and CD25 (high-affinity IL-2 receptor alpha chain) and secrete anti-inflammatory cytokines IL-10 and TGF-beta.
32	What distinguishes Acute cellular rejection from Acute humoral (antibody-mediated) rejection in organ transplantation?	Acute cellular rejection is mediated by host T lymphocytes (CD8+ CTLs and CD4+ Th cells) invading graft parenchyma (endothelialitis/tubulitis); acute humoral rejection involves de novo donor-specific antibodies and C4d complement split-product deposition.