Immunology Test 1: Chapters 1-6

All MCQ from Chapters 1-6; given set of answers was a-e, but due to Knowt only allowing a-d, one answer choice was left off for each question.

Which of the following cells are primarily involved in the immune system's immunosurveillance function? 

T Lymphocytes

Which of the following components is primarily involved in barriers to primary infection? 

Phagocytes

Which of the following is a potential consequence of the immune system failing to distinguish self from non-self? 

Autoimmunity Immunity to microbes 

Which of the following components of the immune system serves as both a physical and chemical barrier to pathogens?

Skin

Which of the following scenarios best illustrates the concept of immunity?

A vaccinated individual not contracting a disease despite exposure to the pathogen

Which of the following is an example of how pathogens cause disease?

By evading the immune response and multiplying within the host

What could be a potential reason for the relatively high number of recent Hepatitis B cases despite vaccination efforts?

Low vaccination coverage in certain populations

Which of the following best describes the role of phagocytes in the immune system?

They engulf and destroy pathogens through phagocytosis.

What is the main advantage of the adaptive immune system over the non-specific defenses?

It creates memory cells for long-term immunity.

Which of the following is an example of a non-specific immune response?

Inflammation at the site of infection

Which type of immunity is acquired through vaccination?

Artificial active immunity

How is active artificial immunity primarily achieved? 

 Exposure to weakened or killed pathogens 

Which of the following best describes naturally-acquired active immunity?

Antigens enter the body naturally, stimulating an immune response.

Which of the following scenarios best illustrates naturally-acquired passive immunity?

A fetus receiving antibodies through the placenta.

Why does naturally-acquired active immunity provide long-term protection?

It stimulates the production of memory cells.

Which type of immunity is acquired through vaccination?

Artificial active immunity

How does naturally-acquired passive immunity differ from naturally-acquired active immunity in terms of duration of protection?

Naturally-acquired passive immunity provides short-term protection.

Which of the following is a characteristic of naturally-acquired active immunity?

It results from the natural exposure to antigens.

Why is naturally-acquired passive immunity important for newborns?

It provides immediate, temporary protection against infections.

Which of the following best explains why breast milk is beneficial for an infant's immunity?

It provides pre-formed antibodies that offer immediate protection.

Which of the following best explains the immediate protection provided by artificially-acquired passive immunity?

It provides pre-formed antibodies that neutralize pathogens.

What is the main advantage of the adaptive immune system over the non-specific defenses?

It creates memory cells for long-term immunity.

What is a characteristic feature of adaptive immunity? 

Specific recognition of antigens 

Which of the following cell types is derived from the myeloid lineage? 

Polymorphonuclear neutrophils (PMNs) 

What is the main reason for the higher potency of adaptive immunity compared to innate immunity? 

Formation of memory cells 

Where do lymphocytes undergo the final stages of antigen-dependent activation? 

Secondary lymphatic organs and tissues

What is the primary function of lymphatic vessels in the body? 

Drainage of lymph fluid from extracellular spaces 

Where do lymphatic vessels ultimately empty into the bloodstream? 

Thoracic duct

Which of the following is a primary function of lymph nodes? 

Filtration of lymph 

A 62-year-old man presents with fever, hypotension, and confusion two days after a urinary tract infection. Blood cultures later grow Escherichia coli. Laboratory studies show markedly elevated TNF-α and IL-1β levels. The initial immune recognition that triggered this cytokine release occurred at the plasma membrane of innate immune cells.

Which receptor is most directly responsible for sensing the microbial product that initiated this response?

TLR4–MD2 complex

A 7-year-old child presents with fever, myalgias, and cough. Nasopharyngeal PCR confirms influenza A infection. Plasmacytoid dendritic cells produce large amounts of type I interferons shortly after viral uptake into endosomes.

Which innate immune receptor is most directly responsible for initiating this antiviral interferon response?

TLR7

A researcher studies macrophages lacking a functional TIR domain in their Toll-like receptors. These cells can bind microbial ligands normally but fail to produce inflammatory cytokines after exposure.

Which downstream process is most directly impaired in these macrophages?

Activation of NF-κB–dependent gene transcription

A 6-year-old boy presents with recurrent episodes of high fever, urticarial rash, conjunctivitis, and arthralgia since infancy. Episodes occur without identifiable infection and are accompanied by markedly elevated CRP and serum amyloid A levels. Genetic testing reveals a mutation affecting an innate immune signaling protein. Treatment with anakinra leads to dramatic symptom resolution.

Which mechanism best explains this patient’s disease?

Excessive activation of the NLRP3 inflammasome leading to overproduction of IL-1β

A 55-year-old man with a history of hypertension presents with sudden onset of severe pain, redness, and swelling of the first metatarsophalangeal joint. Synovial fluid analysis reveals needle-shaped, negatively birefringent crystals. Laboratory studies show elevated serum uric acid.

Which innate immune mechanism is primarily responsible for the intense inflammation in this condition?

NLRP3 inflammasome activation by monosodium urate crystals leading to IL-1β release

A 63-year-old man with hyperlipidemia and type 2 diabetes undergoes coronary angiography revealing significant atherosclerotic plaque burden. Histologic examination of plaques shows macrophages, necrotic cores, and cholesterol crystals. Experimental studies demonstrate IL-1β production within plaques.

Which mechanism best explains the inflammatory component of this patient’s atherosclerosis?

 Activation of the NLRP3 inflammasome by cholesterol crystals in macrophages

A 24-year-old graduate student develops fever, myalgias, and malaise after returning from a conference. PCR testing confirms infection with an RNA virus that replicates in the cytoplasm. Infected cells rapidly produce type I interferons despite normal endosomal TLR function. Further analysis shows intact viral RNA recognition but loss of downstream signaling at the mitochondrial membrane.

Which molecule is most directly responsible for transmitting the antiviral signal from the RNA sensor to downstream transcription factors?

MAVS

A 40-year-old immunocompromised patient develops a disseminated infection with a DNA virus. Infected cells show accumulation of microbial double-stranded DNA in the cytosol, followed by robust type I interferon production. Genetic testing reveals normal IRF3 but impaired synthesis of a cyclic dinucleotide second messenger.

Which enzyme is most likely defective in this patient?

cGAS

A team studies macrophages exposed to intracellular bacteria that produce cyclic di-AMP. Despite normal uptake of bacteria, mutant cells fail to induce type I interferon gene transcription. Molecular analysis shows failure of IRF3 phosphorylation and nuclear translocation.

Which signaling molecule is most directly required upstream of IRF3 in this pathway?

TBK1

Epithelia in Innate Immunity: A 23-year-old woman develops infectious diarrhea after traveling abroad. Stool studies show no invasion beyond the intestinal epithelium, yet inflammation is present. Biopsy reveals intact tight junctions and increased secretion of antimicrobial peptides by epithelial cells.

Which epithelial function is most directly responsible for limiting microbial invasion in this patient?

Production of defensins and cathelicidins

A patient with acute bacterial pneumonia has a marked leukocytosis. Peripheral blood smear shows numerous cells with multilobed nuclei and pale cytoplasmic granules.

Which feature best distinguishes these cells from monocytes?

Presence of a multilobed nucleus

A researcher studies macrophages isolated from adult liver tissue. These cells show long-term self-renewal and are present even in the absence of ongoing inflammation.

What is the most likely developmental origin of these macrophages?

Fetal yolk sac or liver precursors

A macrophage encounters intracellular bacteria. NK cells in the surrounding tissue secrete interferon-γ (IFN-γ).

Which macrophage response is most directly induced by IFN-γ in innate immunity?

Increased expression of inducible nitric oxide synthase (iNOS)

NK Cells as Killers of Infected Host Cells: A 41-year-old man develops a viral infection. Tissue biopsy shows host cells harboring intracellular virus. Despite minimal antibody production early in infection, many infected cells undergo apoptosis.

Which immune cell type is primarily responsible for eliminating these infected host cells at this stage?

Natural killer (NK) cells

A patient with an intracellular bacterial infection shows impaired macrophage killing despite intact phagocytosis. Laboratory studies reveal defective interferon-γ (IFN-γ) production.

Which upstream signal is most likely deficient in this patient?

IL-12 secretion by macrophages

A tumor cell line is found to downregulate class I MHC expression while upregulating stress-induced ligands. When co-cultured with NK cells, these tumor cells are efficiently lysed.

What is the primary mechanism allowing NK cells to kill these tumor cells?

Reduced inhibitory signaling with dominant activating receptor engagement

Lectin Pathway of Complement Activation:

A 6-year-old child presents with recurrent respiratory infections. Laboratory testing reveals low levels of a plasma protein that normally binds microbial carbohydrates and activates complement without the need for antibodies.

Deficiency of which molecule best explains this finding?

Mannose-binding lectin (MBL)

A patient with Neisseria meningitidis bacteremia is found to have a genetic deficiency in a late complement component.

Which immune defect most directly predisposes this patient to infection with thin-walled bacteria?

Inability to form the membrane attack complex (MAC)

A hospitalized patient with severe pneumonia shows markedly elevated serum C-reactive protein (CRP) levels within 48 hours of infection onset.

What is the most important immunologic function of CRP in this setting?

Opsonization of microbes and activation of the classical complement pathway

Cytokines Driving Acute Inflammation

A 54-year-old man presents with fever, hypotension, and leukocytosis shortly after developing a gram-negative bacterial infection. Blood cultures are positive, and his symptoms reflect a strong systemic inflammatory response.

Which cytokine is most directly responsible for fever, endothelial activation, and leukocyte recruitment in this patient?

Tumor necrosis factor (TNF)

A patient with an intracellular bacterial infection has macrophages that efficiently phagocytose bacteria but fail to kill them. Further testing shows defective natural killer (NK) cell activation.

Which macrophage-derived cytokine is most likely deficient?

Interleukin-12 (IL-12)

A patient infected with a novel RNA virus shows rapid induction of an antiviral state in neighboring uninfected cells, limiting viral replication before adaptive immunity develops.

Which cytokines are primarily responsible for this early antiviral effect?

Type I interferons (IFN-α, IFN-β)

A patient with a localized skin infection develops marked neutrophil accumulation at the site of infection within hours. Endothelial cells near the infection show increased adhesion molecule expression.

Which class of cytokines is most directly responsible for guiding leukocytes to this infected tissue?

Chemokines

A patient recovering from sepsis shows declining inflammatory markers despite persistence of microbial antigens. Macrophage cytokine production is markedly reduced.

Which cytokine is most likely responsible for suppressing excessive innate immune activation?

Interleukin-10 (IL-10)

A tissue biopsy from a chronically inflamed site shows cytokines that suppress immune activation while promoting fibrosis and tissue repair. These cytokines are produced by both innate immune cells and T lymphocytes.

Which cytokine best fits this description?

Transforming growth factor-β (TGF-β)

Recurrent Bacterial Infections Without Pus

A 6-month-old infant presents with recurrent skin and mucosal bacterial infections, poor wound healing, and absence of pus formation. The umbilical cord detached at 5 weeks of age. Laboratory studies show marked neutrophilia but minimal neutrophil accumulation at sites of infection.

Which step in leukocyte recruitment is most directly impaired in this condition?

Firm adhesion mediated by β2 integrins

A 45-year-old man sustains a laceration to his forearm while gardening. Within minutes, the surrounding tissue becomes red, warm, and swollen. Microscopic examination of the affected area shows increased leakage of plasma proteins into the interstitial space, including complement components.

Which mediator is most directly responsible for the increased vascular permeability observed at this early stage of inflammation?

Histamine

Defective Antiviral State: A 28-year-old woman presents with severe, recurrent viral respiratory infections since adolescence, including influenza and RSV, but has no history of recurrent bacterial or fungal infections. Laboratory studies show normal lymphocyte counts and immunoglobulin levels. Molecular analysis reveals impaired signaling downstream of the type I interferon receptor.

Which antiviral mechanism is most directly impaired in this patient?

Induction of enzymes that inhibit viral protein translation and degrade viral RNA

A novel RNA virus is found to cause prolonged infection despite early innate immune activation. Infected cells show reduced expression of interferon-stimulated genes, even though type I interferons are detectable in serum. Viral protein analysis reveals a factor that blocks host STAT phosphorylation.

Which immune evasion strategy best explains this finding?

Inhibition of type I interferon receptor signaling by blocking STAT activation

A 45-year-old man recovers from a severe viral infection but later develops prolonged immune suppression with poor macrophage activation and reduced inflammatory cytokine production. Laboratory analysis shows elevated IL-10 levels and increased expression of suppressors of cytokine signaling (SOCS) proteins in macrophages.

Which mechanism best explains the downregulation of innate immune responses in this patient?

IL-10–mediated inhibition of macrophage activation and SOCS blockade of cytokine signaling

Role of Innate Immunity in T-Cell Activation

A 28-year-old woman develops a bacterial skin infection. Dendritic cells at the site of infection recognize microbial products and migrate to regional lymph nodes, where they efficiently activate naïve T cells.

Which molecule on the dendritic cell provides the critical second signal required for T-cell activation?

B7 (CD80/CD86)

A medical student studies B-cell responses to protein antigens. She observes that B cells binding soluble antigen via the B-cell receptor do not undergo class switching unless additional signals are present.

Which interaction provides the critical second signal for full activation of B cells responding to protein antigens?

CD40 on B cells binding CD40L on helper T cells

A 4-year-old boy is brought to the clinic with his third episode of oral candidiasis (thrush) in 6 months. His medical history is significant for two previous episodes of cutaneous fungal infections requiring prolonged antifungal therapy. Physical examination reveals white plaques on the oral mucosa and some erythematous skin lesions. His parents report he has had normal recovery from bacterial and viral infections, and his vaccination history is up to date. 

•Laboratory: normal complete blood count, immunoglobulin levels (IgG, IgA, IgM), T-cell and B-cell counts, neutrophil oxidative burst test 

•Genetic testing reveals a mutation affecting a pattern recognition receptor that specifically recognizes β-glucans in fungal cell walls. 

Which pattern recognition receptor is most likely defective in this patient? 

Dectin-1 

A 4-year-old boy is brought to the clinic with his third episode of oral candidiasis (thrush) in 6 months. His medical history is significant for two previous episodes of cutaneous fungal infections requiring prolonged antifungal therapy. Physical examination reveals white plaques on the oral mucosa and some erythematous skin lesions. His parents report he has had normal recovery from bacterial and viral infections, and his vaccination history is up to date. 

•Laboratory: normal complete blood count, immunoglobulin levels (IgG, IgA, IgM), T-cell and B-cell counts, neutrophil oxidative burst test 

•Genetic testing reveals a mutation affecting a pattern recognition receptor that specifically recognizes β-glucans in fungal cell walls. 

Following recognition of fungal β-glucans, which signaling outcome is most directly initiated by this receptor? 

Phagocytosis and production of reactive oxygen species 

A 4-year-old boy is brought to the clinic with his third episode of oral candidiasis (thrush) in 6 months. His medical history is significant for two previous episodes of cutaneous fungal infections requiring prolonged antifungal therapy. Physical examination reveals white plaques on the oral mucosa and some erythematous skin lesions. His parents report he has had normal recovery from bacterial and viral infections, and his vaccination history is up to date. 

•Laboratory: normal complete blood count, immunoglobulin levels (IgG, IgA, IgM), T-cell and B-cell counts, neutrophil oxidative burst test 

•Genetic testing reveals a mutation affecting a pattern recognition receptor that specifically recognizes β-glucans in fungal cell walls. 

This patient's normal response to bacterial and viral infections despite recurrent fungal disease is best explained by which principle? 

Different pattern recognition receptors show specificity for distinct microbial components 

A 4-year-old boy is brought to the clinic with his third episode of oral candidiasis (thrush) in 6 months. His medical history is significant for two previous episodes of cutaneous fungal infections requiring prolonged antifungal therapy. Physical examination reveals white plaques on the oral mucosa and some erythematous skin lesions. His parents report he has had normal recovery from bacterial and viral infections, and his vaccination history is up to date. 

•Laboratory: normal complete blood count, immunoglobulin levels (IgG, IgA, IgM), T-cell and B-cell counts, neutrophil oxidative burst test 

•Genetic testing reveals a mutation affecting a pattern recognition receptor that specifically recognizes β-glucans in fungal cell walls. 

In addition to impaired fungal recognition, patients with this receptor deficiency are at increased risk for which inflammatory complication? 

Severe inflammatory bowel disease 

A 34-year-old previously healthy woman presents to the emergency department with a 3-day history of productive cough, fever (39.2°C), and pleuritic chest pain. She recently returned from a camping trip where she cleaned out an old barn. Chest X-ray reveals a dense right lower lobe infiltrate with a small pleural effusion. Blood cultures grow Streptococcus pneumoniae. Despite appropriate antibiotic therapy, her fever persists and inflammatory markers remain elevated. 

Bronchoalveolar lavage (BAL):  Abundant neutrophils and alveolar macrophages. Bacteria within phagocytes. High levels of TNF, IL-1, and IL-8 in BAL fluid. C3b deposition on bacterial surfaces. Increased expression of B7 molecules on dendritic cells 

Laboratory:  WBC: 18,000/μL (75% neutrophils, 15% lymphocytes). CRP: 150 mg/L (markedly elevated). Serum C3: decreased. S. pneumoniae strain lacks a polysaccharide capsule (an unusual variant).

The alveolar macrophages in this patient's lungs are most likely derived from which developmental origin? 

Fetal liver or yolk sac precursors established during development 

A 34-year-old previously healthy woman presents to the emergency department with a 3-day history of productive cough, fever (39.2°C), and pleuritic chest pain. She recently returned from a camping trip where she cleaned out an old barn. Chest X-ray reveals a dense right lower lobe infiltrate with a small pleural effusion. Blood cultures grow Streptococcus pneumoniae. Despite appropriate antibiotic therapy, her fever persists and inflammatory markers remain elevated. 

Bronchoalveolar lavage (BAL):  Abundant neutrophils and alveolar macrophages. Bacteria within phagocytes. High levels of TNF, IL-1, and IL-8 in BAL fluid. C3b deposition on bacterial surfaces. Increased expression of B7 molecules on dendritic cells 

Laboratory:  WBC: 18,000/μL (75% neutrophils, 15% lymphocytes). CRP: 150 mg/L (markedly elevated). Serum C3: decreased. S. pneumoniae strain lacks a polysaccharide capsule (an unusual variant). 

The absence of a polysaccharide capsule in this S. pneumoniae strain most directly affects which aspect of innate immunity?

Resistance to phagocytosis by neutrophils and macrophages 

A 34-year-old previously healthy woman presents to the emergency department with a 3-day history of productive cough, fever (39.2°C), and pleuritic chest pain. She recently returned from a camping trip where she cleaned out an old barn. Chest X-ray reveals a dense right lower lobe infiltrate with a small pleural effusion. Blood cultures grow Streptococcus pneumoniae. Despite appropriate antibiotic therapy, her fever persists and inflammatory markers remain elevated. 

Bronchoalveolar lavage (BAL):  Abundant neutrophils and alveolar macrophages. Bacteria within phagocytes. High levels of TNF, IL-1, and IL-8 in BAL fluid. C3b deposition on bacterial surfaces. Increased expression of B7 molecules on dendritic cells 

Laboratory:  WBC: 18,000/μL (75% neutrophils, 15% lymphocytes). CRP: 150 mg/L (markedly elevated). Serum C3: decreased. S. pneumoniae strain lacks a polysaccharide capsule (an unusual variant). 

The decreased serum C3 levels in this patient most likely indicate which immunologic process?

Consumption of C3 due to ongoing complement activation at the infection site 

A 34-year-old previously healthy woman presents to the emergency department with a 3-day history of productive cough, fever (39.2°C), and pleuritic chest pain. She recently returned from a camping trip where she cleaned out an old barn. Chest X-ray reveals a dense right lower lobe infiltrate with a small pleural effusion. Blood cultures grow Streptococcus pneumoniae. Despite appropriate antibiotic therapy, her fever persists and inflammatory markers remain elevated. 

Bronchoalveolar lavage (BAL):  Abundant neutrophils and alveolar macrophages. Bacteria within phagocytes. High levels of TNF, IL-1, and IL-8 in BAL fluid. C3b deposition on bacterial surfaces. Increased expression of B7 molecules on dendritic cells 

Laboratory:  WBC: 18,000/μL (75% neutrophils, 15% lymphocytes). CRP: 150 mg/L (markedly elevated). Serum C3: decreased. S. pneumoniae strain lacks a polysaccharide capsule (an unusual variant). 

The increased expression of B7 molecules on dendritic cells in the BAL fluid indicates preparation for which immunologic function? 

Provision of costimulatory signals for T-cell activation 

A 19-year-old man presents with his third severe herpes simplex virus (HSV) infection this year. Despite normal CD4+ and CD8+ T cell counts and immunoglobulin levels, he experiences prolonged viral shedding. Genetic testing reveals a homozygous mutation in the gene encoding MAVS (mitochondrial antiviral signaling protein). Viral culture from his lesions shows high HSV titers. Laboratory analysis of his infected fibroblasts demonstrates normal TLR expression but impaired interferon-β production following cytosolic viral RNA detection.

The patient's MAVS deficiency most directly impairs which antiviral pathway? 

RIG-I/MDA5 cytosolic RNA sensor signaling to produce type I interferons 

A 19-year-old man presents with his third severe herpes simplex virus (HSV) infection this year. Despite normal CD4+ and CD8+ T cell counts and immunoglobulin levels, he experiences prolonged viral shedding. Genetic testing reveals a homozygous mutation in the gene encoding MAVS (mitochondrial antiviral signaling protein). Viral culture from his lesions shows high HSV titers. Laboratory analysis of his infected fibroblasts demonstrates normal TLR expression but impaired interferon-β production following cytosolic viral RNA detection. 

Which interferon-stimulated gene function is most impaired in this patient's cells?

Inhibition of viral protein synthesis and RNA degradation 

A 19-year-old man presents with his third severe herpes simplex virus (HSV) infection this year. Despite normal CD4+ and CD8+ T cell counts and immunoglobulin levels, he experiences prolonged viral shedding. Genetic testing reveals a homozygous mutation in the gene encoding MAVS (mitochondrial antiviral signaling protein). Viral culture from his lesions shows high HSV titers. Laboratory analysis of his infected fibroblasts demonstrates normal TLR expression but impaired interferon-β production following cytosolic viral RNA detection. 

NK cells in this patient would still kill HSV-infected cells through which mechanism?

Recognition of reduced MHC class I and engagement of activating receptors 

A 19-year-old man presents with his third severe herpes simplex virus (HSV) infection this year. Despite normal CD4+ and CD8+ T cell counts and immunoglobulin levels, he experiences prolonged viral shedding. Genetic testing reveals a homozygous mutation in the gene encoding MAVS (mitochondrial antiviral signaling protein). Viral culture from his lesions shows high HSV titers. Laboratory analysis of his infected fibroblasts demonstrates normal TLR expression but impaired interferon-β production following cytosolic viral RNA detection. 

Despite impaired type I interferon production, which innate immune component could still combat this patient's HSV infection?

Plasmacytoid dendritic cells producing IFN-α via endosomal TLR9 

A 4-year-old boy presents to the emergency department with high fever (40°C), generalized urticarial rash, conjunctival injection, and severe joint pain affecting his knees and ankles. His parents report similar episodes occurring every 4-6 weeks since infancy, each lasting 2-3 days. Between episodes, he appears completely healthy. Laboratory studies during the acute episode show: WBC 22,000/μL, CRP 180 mg/L, ESR 95 mm/hr, and serum amyloid A markedly elevated. Blood and urine cultures are negative. Genetic testing reveals a gain-of-function mutation in NLRP3. Treatment with anakinra (IL-1 receptor antagonist) results in rapid resolution of symptoms within 24 hours.

The gain-of-function NLRP3 mutation in this patient most directly results in which pathologic process?

Constitutive activation of the inflammasome leading to excessive IL-1β production 

A 4-year-old boy presents to the emergency department with high fever (40°C), generalized urticarial rash, conjunctival injection, and severe joint pain affecting his knees and ankles. His parents report similar episodes occurring every 4-6 weeks since infancy, each lasting 2-3 days. Between episodes, he appears completely healthy. Laboratory studies during the acute episode show: WBC 22,000/μL, CRP 180 mg/L, ESR 95 mm/hr, and serum amyloid A markedly elevated. Blood and urine cultures are negative. Genetic testing reveals a gain-of-function mutation in NLRP3. Treatment with anakinra (IL-1 receptor antagonist) results in rapid resolution of symptoms within 24 hours.

Why does anakinra effectively treat this patient's symptoms?

It blocks IL-1 signaling, preventing downstream inflammatory effects of excessive IL-1β 

A 4-year-old boy presents to the emergency department with high fever (40°C), generalized urticarial rash, conjunctival injection, and severe joint pain affecting his knees and ankles. His parents report similar episodes occurring every 4-6 weeks since infancy, each lasting 2-3 days. Between episodes, he appears completely healthy. Laboratory studies during the acute episode show: WBC 22,000/μL, CRP 180 mg/L, ESR 95 mm/hr, and serum amyloid A markedly elevated. Blood and urine cultures are negative. Genetic testing reveals a gain-of-function mutation in NLRP3. Treatment with anakinra (IL-1 receptor antagonist) results in rapid resolution of symptoms within 24 hours.

The markedly elevated serum amyloid A during acute episodes represents which type of immune response?

Acute-phase response triggered by IL-1 and IL-6 inducing hepatic protein synthesis 

A 4-year-old boy presents to the emergency department with high fever (40°C), generalized urticarial rash, conjunctival injection, and severe joint pain affecting his knees and ankles. His parents report similar episodes occurring every 4-6 weeks since infancy, each lasting 2-3 days. Between episodes, he appears completely healthy. Laboratory studies during the acute episode show: WBC 22,000/μL, CRP 180 mg/L, ESR 95 mm/hr, and serum amyloid A markedly elevated. Blood and urine cultures are negative. Genetic testing reveals a gain-of-function mutation in NLRP3. Treatment with anakinra (IL-1 receptor antagonist) results in rapid resolution of symptoms within 24 hours.

Between symptomatic episodes, which regulatory mechanism most likely prevents continuous inflammation despite the persistent NLRP3 mutation?

Negative feedback by IL-10 and posttranslational modifications that inhibit inflammasome assembly 

A 7-month-old infant is referred to pediatric immunology for recurrent soft tissue infections without pus formation. Her umbilical cord separated at 6 weeks of age (normal: 7-14 days). She has had three episodes of bacterial skin infections and one episode of periodontal inflammation despite appropriate antibiotics. Physical examination reveals multiple healing skin ulcers with minimal inflammatory response. Complete blood count shows persistent leukocytosis (WBC 35,000/μL) with 80% neutrophils, even between infections. Flow cytometry of peripheral blood leukocytes reveals absent CD18 expression. Parents report that wounds heal slowly and without typical purulent discharge. Bacterial cultures from skin lesions grow Staphylococcus aureus. 

The absence of CD18 expression on this patient's leukocytes most directly impairs which step in neutrophil recruitment to infected tissues?

Integrin-mediated firm adhesion to endothelial cells 

A 7-month-old infant is referred to pediatric immunology for recurrent soft tissue infections without pus formation. Her umbilical cord separated at 6 weeks of age (normal: 7-14 days). She has had three episodes of bacterial skin infections and one episode of periodontal inflammation despite appropriate antibiotics. Physical examination reveals multiple healing skin ulcers with minimal inflammatory response. Complete blood count shows persistent leukocytosis (WBC 35,000/μL) with 80% neutrophils, even between infections. Flow cytometry of peripheral blood leukocytes reveals absent CD18 expression. Parents report that wounds heal slowly and without typical purulent discharge. Bacterial cultures from skin lesions grow Staphylococcus aureus. 

Why does this patient exhibit persistent leukocytosis despite recurrent infections?

Neutrophils cannot exit the bloodstream to reach infection sites, accumulating in circulation 

A 7-month-old infant is referred to pediatric immunology for recurrent soft tissue infections without pus formation. Her umbilical cord separated at 6 weeks of age (normal: 7-14 days). She has had three episodes of bacterial skin infections and one episode of periodontal inflammation despite appropriate antibiotics. Physical examination reveals multiple healing skin ulcers with minimal inflammatory response. Complete blood count shows persistent leukocytosis (WBC 35,000/μL) with 80% neutrophils, even between infections. Flow cytometry of peripheral blood leukocytes reveals absent CD18 expression. Parents report that wounds heal slowly and without typical purulent discharge. Bacterial cultures from skin lesions grow Staphylococcus aureus. 

The delayed umbilical cord separation in this patient is explained by which immune defect?

Impaired neutrophil migration to the umbilical stump to facilitate physiologic detachment 

A 7-month-old infant is referred to pediatric immunology for recurrent soft tissue infections without pus formation. Her umbilical cord separated at 6 weeks of age (normal: 7-14 days). She has had three episodes of bacterial skin infections and one episode of periodontal inflammation despite appropriate antibiotics. Physical examination reveals multiple healing skin ulcers with minimal inflammatory response. Complete blood count shows persistent leukocytosis (WBC 35,000/μL) with 80% neutrophils, even between infections. Flow cytometry of peripheral blood leukocytes reveals absent CD18 expression. Parents report that wounds heal slowly and without typical purulent discharge. Bacterial cultures from skin lesions grow Staphylococcus aureus. 

Despite absent pus formation, which innate immune mechanism can still provide partial protection against S. aureus in this patient?

Tissue-resident macrophages recognizing bacteria via TLR2 and producing cytokines 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

Formation of the membrane attack complex to lyse bacteria 

Formation of the membrane attack complex to lyse bacteria 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

Why is this patient particularly susceptible to Neisseria species rather than other encapsulated bacteria?

Neisseria have thin cell walls making them uniquely dependent on MAC for killing 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

Despite absent C9, which complement-mediated function remains intact in this patient?

C3b-mediated opsonization enhancing phagocytosis by neutrophils 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

After recovering from this acute infection, the patient's dendritic cells present meningococcal antigens to T cells in lymph nodes. Which molecule provides the critical second signal for T cell activation?

B7 (CD80/CD86) engaging CD28 on T cells 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

The absence of C9 in this patient most directly impairs which antimicrobial mechanism?

Formation of the membrane attack complex to lyse bacteria 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

Why is this patient particularly susceptible to Neisseria species rather than other encapsulated bacteria?

Neisseria have thin cell walls making them uniquely dependent on MAC for killing 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

Despite absent C9, which complement-mediated function remains intact in this patient?

C3b-mediated opsonization enhancing phagocytosis by neutrophils 

A 16-year-old girl presents with her second episode of Neisseria meningitidis bacteremia in 18 months. She was previously healthy until age 14 when she had her first episode of meningococcal meningitis, from which she fully recovered. Current presentation includes fever (39.5°C), headache, petechial rash, and neck stiffness. Blood cultures are positive for N. meningitidis serogroup Y. Immunologic workup reveals: normal immunoglobulin levels, normal T and B cell counts, normal neutrophil oxidative burst, and intact C3 levels. However, CH50 (total hemolytic complement) is undetectable. Detailed complement testing shows absent C9 with normal C1-C8 levels. Her neutrophils demonstrate normal phagocytosis of opsonized bacteria, and C3b deposition on bacterial surfaces is intact. 

After recovering from this acute infection, the patient's dendritic cells present meningococcal antigens to T cells in lymph nodes. Which molecule provides the critical second signal for T cell activation?

B7 (CD80/CD86) engaging CD28 on T cells 

An 8-year-old boy presents with his fourth deep-seated abscess in 2 years, currently involving his left axilla. Previous abscesses required surgical drainage and grew Staphylococcus aureus, Serratia marcescens, and Aspergillus species. Despite appropriate antibiotics, infections persist with granuloma formation on histology showing macrophages surrounding viable bacteria. Laboratory studies show: normal WBC count, normal immunoglobulin levels, normal complement (CH50), and normal lymphocyte proliferation. Nitroblue tetrazolium (NBT) test is abnormal—neutrophils fail to reduce the dye. Dihydrorhodamine (DHR) flow cytometry confirms absent oxidative burst. Genetic testing reveals a mutation in CYBB encoding gp91-phox. Despite intact phagocytosis, his neutrophils cannot kill catalase-positive organisms. 

The granuloma formation in this patient's abscesses results from which pathologic mechanism?

Persistent intracellular microbes due to failed oxidative killing triggering chronic macrophage activation 

An 8-year-old boy presents with his fourth deep-seated abscess in 2 years, currently involving his left axilla. Previous abscesses required surgical drainage and grew Staphylococcus aureus, Serratia marcescens, and Aspergillus species. Despite appropriate antibiotics, infections persist with granuloma formation on histology showing macrophages surrounding viable bacteria. Laboratory studies show: normal WBC count, normal immunoglobulin levels, normal complement (CH50), and normal lymphocyte proliferation. Nitroblue tetrazolium (NBT) test is abnormal—neutrophils fail to reduce the dye. Dihydrorhodamine (DHR) flow cytometry confirms absent oxidative burst. Genetic testing reveals a mutation in CYBB encoding gp91-phox. Despite intact phagocytosis, his neutrophils cannot kill catalase-positive organisms. 

Why does this patient specifically have infections with catalase-positive organisms like S. aureus and Aspergillus?

Catalase neutralizes hydrogen peroxide, preventing both host and microbial ROS from killing bacteria 

An 8-year-old boy presents with his fourth deep-seated abscess in 2 years, currently involving his left axilla. Previous abscesses required surgical drainage and grew Staphylococcus aureus, Serratia marcescens, and Aspergillus species. Despite appropriate antibiotics, infections persist with granuloma formation on histology showing macrophages surrounding viable bacteria. Laboratory studies show: normal WBC count, normal immunoglobulin levels, normal complement (CH50), and normal lymphocyte proliferation. Nitroblue tetrazolium (NBT) test is abnormal—neutrophils fail to reduce the dye. Dihydrorhodamine (DHR) flow cytometry confirms absent oxidative burst. Genetic testing reveals a mutation in CYBB encoding gp91-phox. Despite intact phagocytosis, his neutrophils cannot kill catalase-positive organisms. 

Despite defective oxidative burst, which antimicrobial mechanism can still partially protect this patient?

Lysosomal enzymes in phagolysosomes degrading bacterial components 

An 8-year-old boy presents with his fourth deep-seated abscess in 2 years, currently involving his left axilla. Previous abscesses required surgical drainage and grew Staphylococcus aureus, Serratia marcescens, and Aspergillus species. Despite appropriate antibiotics, infections persist with granuloma formation on histology showing macrophages surrounding viable bacteria. Laboratory studies show: normal WBC count, normal immunoglobulin levels, normal complement (CH50), and normal lymphocyte proliferation. Nitroblue tetrazolium (NBT) test is abnormal—neutrophils fail to reduce the dye. Dihydrorhodamine (DHR) flow cytometry confirms absent oxidative burst. Genetic testing reveals a mutation in CYBB encoding gp91-phox. Despite intact phagocytosis, his neutrophils cannot kill catalase-positive organisms. 

Macrophages in this patient's granulomas would show enhanced killing if stimulated with which cytokine?

IFN-γ, which induces nitric oxide synthase for ROS-independent killing 

A 58-year-old diabetic woman with a urinary tract infection rapidly deteriorates, developing fever (40.1°C), hypotension (BP 75/40), confusion, and diffuse petechiae. Blood cultures grow Escherichia coli. Despite broad-spectrum antibiotics, she develops multi-organ dysfunction. Laboratory studies show: WBC 28,000/μL with left shift, platelets 45,000/μL, creatinine 3.2 mg/dL, and lactate 6.5 mmol/L. Serum cytokine analysis reveals markedly elevated TNF (500 pg/mL), IL-1β (200 pg/mL), and IL-6 (1000 pg/mL). Surprisingly, IL-10 levels are very low (<5 pg/mL). The patient requires vasopressor support and mechanical ventilation. Genetic testing reveals a polymorphism in the IL10 gene reducing its expression. Her monocytes show sustained NF-κB activation with minimal SOCS protein expression. 

The E. coli lipopolysaccharide (LPS) in this patient's bloodstream is initially recognized by which innate immune receptor complex?

TLR4-MD2 complex on macrophages and dendritic cells 

A 58-year-old diabetic woman with a urinary tract infection rapidly deteriorates, developing fever (40.1°C), hypotension (BP 75/40), confusion, and diffuse petechiae. Blood cultures grow Escherichia coli. Despite broad-spectrum antibiotics, she develops multi-organ dysfunction. Laboratory studies show: WBC 28,000/μL with left shift, platelets 45,000/μL, creatinine 3.2 mg/dL, and lactate 6.5 mmol/L. Serum cytokine analysis reveals markedly elevated TNF (500 pg/mL), IL-1β (200 pg/mL), and IL-6 (1000 pg/mL). Surprisingly, IL-10 levels are very low (<5 pg/mL). The patient requires vasopressor support and mechanical ventilation. Genetic testing reveals a polymorphism in the IL10 gene reducing its expression. Her monocytes show sustained NF-κB activation with minimal SOCS protein expression. 

The low IL-10 levels in this patient most directly contribute to sepsis severity through which mechanism?

Failure to suppress macrophage proinflammatory cytokine production and limit NF-κB activation 

A 58-year-old diabetic woman with a urinary tract infection rapidly deteriorates, developing fever (40.1°C), hypotension (BP 75/40), confusion, and diffuse petechiae. Blood cultures grow Escherichia coli. Despite broad-spectrum antibiotics, she develops multi-organ dysfunction. Laboratory studies show: WBC 28,000/μL with left shift, platelets 45,000/μL, creatinine 3.2 mg/dL, and lactate 6.5 mmol/L. Serum cytokine analysis reveals markedly elevated TNF (500 pg/mL), IL-1β (200 pg/mL), and IL-6 (1000 pg/mL). Surprisingly, IL-10 levels are very low (<5 pg/mL). The patient requires vasopressor support and mechanical ventilation. Genetic testing reveals a polymorphism in the IL10 gene reducing its expression. Her monocytes show sustained NF-κB activation with minimal SOCS protein expression. 

The sustained NF-κB activation with minimal SOCS expression indicates failure of which regulatory mechanism?

Negative feedback suppression of cytokine signaling pathways 

A 58-year-old diabetic woman with a urinary tract infection rapidly deteriorates, developing fever (40.1°C), hypotension (BP 75/40), confusion, and diffuse petechiae. Blood cultures grow Escherichia coli. Despite broad-spectrum antibiotics, she develops multi-organ dysfunction. Laboratory studies show: WBC 28,000/μL with left shift, platelets 45,000/μL, creatinine 3.2 mg/dL, and lactate 6.5 mmol/L. Serum cytokine analysis reveals markedly elevated TNF (500 pg/mL), IL-1β (200 pg/mL), and IL-6 (1000 pg/mL). Surprisingly, IL-10 levels are very low (<5 pg/mL). The patient requires vasopressor support and mechanical ventilation. Genetic testing reveals a polymorphism in the IL10 gene reducing its expression. Her monocytes show sustained NF-κB activation with minimal SOCS protein expression. 

Administration of which therapeutic agent would most directly address the underlying cytokine dysregulation in this patient?

Recombinant IL-10 to restore anti-inflammatory signaling 

A 42-year-old construction worker sustains severe crush injuries to his right leg after a scaffolding collapse. No external wounds are visible, but extensive muscle necrosis is evident on MRI. Despite negative blood cultures and no signs of infection, he develops high fever (39.8°C), severe pain, and marked swelling of the affected limb within 6 hours. Laboratory studies show: WBC 24,000/μL (85% neutrophils), CRP 220 mg/L, and elevated serum lactate dehydrogenase and creatine kinase indicating massive cell death. Tissue biopsy reveals extensive neutrophil infiltration, activated macrophages producing TNF and IL-1β, and marked edema. Immunohistochemistry shows extracellular HMGB1 protein and ATP in the damaged tissue. TLR4 and NLRP3 are highly expressed on infiltrating leukocytes despite absence of bacterial products. Surgical debridement is performed urgently.

The inflammatory response in this patient's injured tissue is primarily triggered by recognition of which molecular pattern? 

Damage-associated molecular patterns (DAMPs) released from necrotic cells 

A 42-year-old construction worker sustains severe crush injuries to his right leg after a scaffolding collapse. No external wounds are visible, but extensive muscle necrosis is evident on MRI. Despite negative blood cultures and no signs of infection, he develops high fever (39.8°C), severe pain, and marked swelling of the affected limb within 6 hours. Laboratory studies show: WBC 24,000/μL (85% neutrophils), CRP 220 mg/L, and elevated serum lactate dehydrogenase and creatine kinase indicating massive cell death. Tissue biopsy reveals extensive neutrophil infiltration, activated macrophages producing TNF and IL-1β, and marked edema. Immunohistochemistry shows extracellular HMGB1 protein and ATP in the damaged tissue. TLR4 and NLRP3 are highly expressed on infiltrating leukocytes despite absence of bacterial products. Surgical debridement is performed urgently. 

Extracellular ATP released from damaged cells in this patient directly activates which innate immune pathway?

NLRP3 inflammasome leading to IL-1β and IL-18 secretion 

A 42-year-old construction worker sustains severe crush injuries to his right leg after a scaffolding collapse. No external wounds are visible, but extensive muscle necrosis is evident on MRI. Despite negative blood cultures and no signs of infection, he develops high fever (39.8°C), severe pain, and marked swelling of the affected limb within 6 hours. Laboratory studies show: WBC 24,000/μL (85% neutrophils), CRP 220 mg/L, and elevated serum lactate dehydrogenase and creatine kinase indicating massive cell death. Tissue biopsy reveals extensive neutrophil infiltration, activated macrophages producing TNF and IL-1β, and marked edema. Immunohistochemistry shows extracellular HMGB1 protein and ATP in the damaged tissue. TLR4 and NLRP3 are highly expressed on infiltrating leukocytes despite absence of bacterial products. Surgical debridement is performed urgently. 

The extracellular HMGB1 detected in damaged tissue functions as a DAMP by binding to which receptor?

TLR4, initiating NF-κB activation and cytokine production