1
Q
What are the three key principles of immune response to microbes?
A
1) Defense is mediated by innate and adaptive immunity. 2) The immune system responds in distinct ways to different microbes. 3) Microbes evade or resist immune effector mechanisms. 4) Tissue injury may be caused by the host response, not the microbe itself.
2
Q
What is the difference between innate and adaptive immunity?
A
Innate immunity: rapid (minutes-hours), non-specific, no memory, includes barriers, phagocytes, complement, NK cells. Adaptive immunity: slow (days), highly specific, has memory, includes B cells (antibodies) and T cells (CD4+/CD8+).
3
Q
List the mechanisms of pathogenicity of Staphylococcus aureus.
A
Skin infections; acute inflammation induced by toxins; cell death caused by pore-forming toxins; systemic: enterotoxin (superantigen)-induced cytokine production by T cells causing skin necrosis, shock, diarrhea.
4
Q
How does Streptococcus pyogenes (Group A Strep) cause disease?
A
Acute inflammation induced by various toxins, e.g., streptolysin O damages cell membranes. Antiphagocytic action of capsular polysaccharides. Causes pharyngitis, impetigo, erysipelas, cellulitis, scarlet fever.
5
Q
How does Streptococcus pneumoniae cause disease?
A
Acute inflammation induced by cell wall constituents; pneumolysin (similar to streptolysin O) damages cell membranes. Causes pneumonia and meningitis.
6
Q
How does Vibrio cholerae cause diarrhea?
A
Cholera toxin ADP-ribosylates G protein subunit, which leads to increased cyclic AMP in intestinal epithelial cells and results in chloride secretion and massive water loss (watery diarrhea).
7
Q
How does Clostridium tetani cause tetanus?
A
Tetanus toxin binds to the motor end plate at neuromuscular junctions and causes irreversible muscle contraction by blocking inhibitory neurotransmitter (GABA and glycine) release.
8
Q
How does Corynebacterium diphtheriae cause disease?
A
Diphtheria toxin ADP-ribosylates elongation factor-2 (EF-2), which inhibits protein synthesis, causing cell death. Forms a pseudomembrane in the pharynx.
9
Q
How do mycobacteria (TB, leprosy) cause tissue damage?
A
Macrophage activation resulting in granulomatous inflammation and tissue destruction. Delayed-type hypersensitivity (Type IV) reaction.
10
Q
How does Listeria monocytogenes cause disease?
A
Listeriolysin damages cell membranes, allowing the bacterium to escape from phagosomes into the cytoplasm and spread cell-to-cell without exiting the extracellular space.
11
Q
How does Epstein-Barr virus (EBV) cause disease?
A
Acute infection: cell lysis with tropism for B lymphocytes. Latent infection: stimulates B cell proliferation, which can lead to lymphomas (Burkitt’s lymphoma, Hodgkin’s lymphoma, post-transplant lymphoproliferative disease).
12
Q
How does Hepatitis B virus (HBV) cause liver damage?
A
Host cytotoxic T lymphocyte (CTL) response to infected hepatocytes – the liver damage is caused by the immune response, not the virus itself.
13
Q
What are the main cellular components of the immune system?
A
Monocytes, macrophages, APCs/DCs, T cells (CD3, CD4, CD8), B cells (CD19), NK cells, basophils, eosinophils, mast cells.
14
Q
What are the main receptor types involved in immune recognition?
A
MHC/HLA (major histocompatibility complex/human leukocyte antigen), TCRs (T-cell receptors), TLRs (Toll-like receptors), Fc receptors, Complement receptors (C3R).
15
Q
What are the main effector molecules of the immune system?
A
Complement proteins, cytokines, humoral mediators (antibodies), proteases (caspases, granzymes, perforins).
16
Q
What is opsonization?
A
The process by which microbial antigens-antibody complexes attach via the Fc portion of Ig or C3b and bind to corresponding FcR and C3R on immune cell surfaces, subsequently activating those cells for phagocytosis and killing.
17
Q
What are the two major pathways of MHC Class I antigen processing for CD8+ T cells in bacterial infections?
A
1) Cross presentation: antigens from phagosomal bacteria are introduced to MHC I molecules in the same cell. 2) Cross priming: antigens from infected macrophages are translocated to dendritic cells in the vicinity via apoptotic blebs.
18
Q
What is cross presentation?
A
A process where ER membranes are recruited to the phagocytic cup, bringing the machinery for MHC class I processing (TAP, proteasomes, MHC I) into close proximity to the intracellular bacterium, allowing peptide loading of MHC I within the phagosome.
19
Q
What is cross priming?
A
A process where infected macrophages undergo apoptosis, forming apoptotic blebs containing bacterial antigens. These blebs are engulfed by dendritic cells, and the antigenic cargo is introduced to MHC I molecules in the DCs for CD8+ T cell activation.
20
Q
Why is cross priming important for mycobacterial infections?
A
Because: 1) Mycobacteria are firmly secluded from the cytoplasm (cannot access classical MHC I pathway), 2) Macrophages lose their antigen-presenting capacity quickly after infection, and 3) Only dendritic cells express CD1 molecules.
21
Q
What is the role of activating Fc receptors (FcR) in intracellular pathogen defense?
A
Engagement of activating FcRs promotes: 1) Phagolysosomal fusion, 2) Cytokine secretion, 3) Antigen presentation on MHC I and II, 4) Enhanced T-cell responses, and 5) Receptor-mediated endocytosis for intracellular degradation.
22
Q
What is the role of inhibitory Fc receptor FcγRIIb?
A
FcγRIIb counteracts effector cell functions triggered through activating receptors, providing a negative feedback mechanism to limit immune responses and prevent excessive tissue damage.
23
Q
What are the principal mechanisms of innate immunity against extracellular bacteria?
A
1) Complement activation, 2) Phagocytosis, 3) Inflammatory response.
24
Q
What is the principal protective adaptive immune response against extracellular bacteria?
A
Humoral immunity (antibody-mediated). Antibodies participate in neutralization, opsonization, and Fc receptor-mediated phagocytosis.
25
How do complements participate in defense against extracellular bacteria?
1) Phagocytosis of C3b-coated bacteria (opsonization), 2) Inflammation (C3a, C5a anaphylatoxins), 3) Bacterial lysis (membrane attack complex – C5b-9).
26
What is the role of CD4+ T cells in defense against extracellular bacteria?
Following APC presentation, CD4+ T cells produce IFNγ (activates macrophages for killing) and TNF (promotes inflammation). They also help B cells produce better antibody responses.
27
What is the major injurious consequence of host response to extracellular bacteria?
Inflammation and septic shock, caused by cytokines (especially TNF, IL-1, IL-6) produced mainly by activated macrophages.
28
What is the major protective immune response against intracellular bacteria?
Cell-mediated immunity (CMI) – specifically macrophage activation by Th1 CD4+ T cells and killing of infected cells by CD8+ CTLs.
29
What are the innate immune actors against intracellular bacteria?
Neutrophils, macrophages, NK cells, and their products (IL-12, IFNγ).
30
What happens when NK cells are depleted or IL-12 is blocked in intracellular bacterial infections?
Proliferation of infection – these are critical for early control before adaptive immunity develops.
31
What are the adaptive immune actors against intracellular bacteria?
Interaction of infected macrophages with T cells via CD40L and IFNγ leads to eradication of infection. T cell depletion leads to proliferation of infection.
32
List the mechanisms of immune evasion by bacteria.
1) Antigenic variation (Neisseria gonorrhoeae, E. coli, Salmonella), 2) Inhibition of complement activation (many bacteria), 3) Resistance to phagocytosis (pneumococcus), 4) Scavenging of reactive oxygen intermediates (catalase-positive staphylococci), 5) Inhibition of phagolysosome formation (M. tuberculosis, Legionella), 6) Inactivating reactive oxygen/nitrogen intermediates (M. leprae), 7) Disruption of phagosome membrane/escape into cytoplasm (Listeria).
33
How does Mycobacterium tuberculosis evade the immune system?
Inhibits phagolysosome formation – prevents fusion of the phagosome with lysosomes, allowing it to survive and replicate within macrophages.
34
How does Listeria monocytogenes evade the immune system?
Disrupts phagosome membrane using hemolysin (listeriolysin O) and escapes into the cytoplasm, where it can spread cell-to-cell without encountering extracellular immune defenses.
35
What is the Two Signal Hypothesis for T-cell activation?
Signal 1: TCR recognition of peptide-MHC complex on APC. Signal 2: Co-stimulation (e.g., CD28 on T cell binding to B7-1/B7-2 (CD80/CD86) on APC). Without Signal 2, T cells become anergic (tolerant) or undergo apoptosis.
36
What happens to T cells that receive Signal 1 (TCR-MHC) without Signal 2 (co-stimulation)?
They become tolerant – either anergic (functionally unresponsive) or undergo apoptosis. This is a mechanism of peripheral tolerance to self-antigens.
37
What are regulatory T cells (Tregs) and what do they produce?
Tregs (CD4+CD25+FoxP3+) are immunosuppressive T cells that produce IL-10 and TGF-β, which suppress immune responses and prevent autoimmunity and excessive tissue damage.
38
What are the major immune inhibitor receptors on B cells, T cells, and NK cells?
B cells: FcγRIIb. T cells: CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). NK cells: KIR (killer cell Ig-like receptors).
39
What is the role of CTLA-4 in T-cell regulation?
CTLA-4 is the high-affinity receptor for B7-1/B7-2 (CD80/CD86) on APCs. B7-CTLA-4 interactions inhibit T-cell responses – acts as a 'brake' on T-cell activation. It is upregulated on activated T cells to prevent overactivation.
40
What is the function of the B7-CD28/CTLA-4 pathway?
Resting APCs express few B7 molecules – fail to activate naive T cells. Microbes activate APCs and stimulate B7 expression – B7-CD28 interactions stimulate T-cell expansion/differentiation. CTLA-4 (upregulated on activated T cells) binds B7 with higher affinity and inhibits T-cell responses.
41
What are cytokines?
Soluble mediators (proteins/peptides) made by a variety of cells that are involved in initiating and turning off immune responses. Some serve as direct effector molecules (e.g., TNFα).
42
What is the Th1/Th2 paradigm?
Th1 and Th2 are two subsets of CD4+ T helper cells that counter-regulate each other. Th1: driven by IL-12, produces IFNγ – important for intracellular pathogens. Th2: driven by IL-4, produces IL-4, IL-5, IL-13 – important for helminths and allergic responses.
43
What transcription factor is necessary for Th1 differentiation?
T-bet (T-box expressed in T cells).
44
What transcription factors are necessary for Th2 differentiation?
GATA-3 and c-Maf.
45
How does IL-4 affect Th1/Th2 balance?
IL-4 promotes Th2 differentiation and suppresses Th1 differentiation. It is produced by Th2 cells and also by mast cells, basophils, and eosinophils.
46
How does IFNγ affect Th1/Th2 balance?
IFNγ promotes Th1 differentiation and suppresses Th2 differentiation. It is produced by Th1 cells and NK cells.
47
What is the outcome of Th1 vs Th2 response in experimental Leishmaniasis?
Th1 response: CURE. Th2 response: PROGRESSION (disease worsens). This is the classic model of Th1/Th2 polarization determining disease outcome.
48
What is the outcome of Th1 vs Th2 response in tuberculosis?
Th1 response: Cure/Prevention. Th2 response: Progression of disease.
49
What is the outcome of Th1 vs Th2 response in atopy (allergic disease)?
Th1: Prevention? Th2: Progression. Atopic individuals have a Th2-skewed immune response.
50
What is the outcome of Th1 vs Th2 response in Type 1 Diabetes (NOD mouse model)?
Th1: Progression. Th2: Prevention.
51
What is the major protective adaptive immune response against viral infections?
Two arms: 1) Antibodies (humoral immunity) – block virus binding and entry into host cells (neutralization). 2) Cytotoxic T lymphocytes (CTLs/CD8+ T cells) – kill infected cells to eliminate the virus reservoir.
52
How are non-cytopathic viruses (e.g., Hepatitis B) cleared from the body?
CTLs kill infected cells. However, in some viral infections, especially with noncytopathic viruses, CTLs may be responsible for tissue injury (the immune response causes the disease, not the virus itself).
53
What is the role of NK cells in viral infections?
NK cells are part of innate immunity against viruses. They attack and kill virus-infected cells without prior sensitization, especially those that have downregulated MHC Class I (a common viral evasion mechanism).
54
What is the role of Type I interferons (IFNα/β) in viral infections?
Type I interferons induce an 'antiviral state' in uninfected cells – upregulating enzymes that degrade viral RNA (2',5'-oligoadenylate synthetase) and inhibit protein synthesis (PKR). They also activate NK cells and dendritic cells.
55
What are the functions of IFNγ?
Macrophage activation (enhanced killing of intracellular pathogens), upregulation of MHC I and II, Th1 differentiation, B cell class switching (to opsonizing and complement-fixing IgG subclasses), antiviral activity, and inhibition of Th2 responses.
56
List the mechanisms of immune evasion by viruses.
1) Antigenic variation (influenza, rhinovirus, HIV). 2) Inhibition of antigen processing/blockade of TAP transporter (herpes simplex). 3) Removal of Class I MHC molecules from the ER (cytomegalovirus – US6, US11 proteins). 4) Production of cytokine receptor homologues (vaccinia – IL-1 receptor; poxviruses – IFNγ receptor; CMV – chemokine receptor). 5) Production of immunosuppressive cytokines (EBV – IL-10 homologue). 6) Infection of immunocompetent cells (HIV – infects CD4+ T cells and macrophages).
57
How does HIV evade the immune system?
Infects and destroys CD4+ T cells (the central orchestrator of adaptive immunity), undergoes rapid antigenic variation (high mutation rate), latently infects resting memory CD4+ T cells (hidden reservoir), and downregulates MHC Class I on infected cells.
58
How does Herpes Simplex Virus (HSV) evade antigen presentation?
Produces ICP47 protein that blocks the TAP (transporter associated with antigen processing) – preventing peptide transport into the ER and thus MHC Class I loading, so infected cells are not recognized by CD8+ CTLs.
59
How does Cytomegalovirus (CMV) evade MHC Class I presentation?
Produces multiple proteins (US2, US3, US6, US11) that cause removal of Class I MHC molecules from the ER and target them for proteasomal degradation – preventing CD8+ T cell recognition.
60
How does Leishmania manipulate macrophage signaling?
Leishmania internalization activates SHP-1 (Src homology phosphatase 1), which negatively affects JAK2, Erk1/Erk2 MAP kinases, NF-κB, IRF-1, and AP-1. This inhibits IFNγ-inducible macrophage functions: nitric oxide (NO) production, IL-12 production, and immunoproteasome formation. STAT1α degradation by proteasome is PKCα-dependent.
61
What is the mechanism of CTL (CD8+ T cell) killing?
Two main mechanisms: 1) Perforin/granzyme pathway: perforin forms pores in target cell membrane; granzymes enter and activate caspases, inducing apoptosis. 2) Fas/FasL pathway: engagement of Fas (CD95) on target cell by FasL on CTL activates caspase-8 and induces apoptosis.
62
What are the four types of immune hypersensitivity reactions (Gell & Coombs classification)?
Type I (Immediate): IgE antibody, mast cells/mediators – anaphylaxis, urticaria, asthma. Type II (Cytotoxic antibodies): IgM/IgG against cell surface antigens – rheumatic fever, autoimmune hemolytic anemia. Type III (Immune Complex): IgM/IgG immune complexes + complement – PSGN, leprosy downgrading reaction, serum sickness. Type IV (T cell mediated): CD4+ DTH or CD8+ CTLs – TB, contact dermatitis, transplant rejection.
63
Give examples of Type I hypersensitivity reactions in tropical diseases.
Peripheral circulatory collapse: ruptured hydatid cyst, trypanosomiasis. Pulmonary infiltration/asthma: tropical eosinophilia, aspergillosis (ABPA). Rashes (urticaria): onchocerciasis (especially treatment reaction), migrating ascaris/strongyloides/hookworm larvae, migrating schistosomula, ground itch (hookworm), swimmers itch (schistosomula), cutaneous larva migrans.
64
Give examples of Type III (immune complex) hypersensitivity reactions in infections.
Shock syndromes: dengue, falciparum malaria, meningococcal infection. Acute glomerulonephritis: streptococcal infection, S. mansoni infection, hepatitis B. Chronic glomerulonephritis: P. malariae malaria, hepatitis B, syphilis. Reticuloendothelial hyperplasia: Tropical Splenomegaly Syndrome (HMS), visceral leishmaniasis, African trypanosomiasis. Local immune complex formation (Arthus reaction): leprosy (ENL), pulmonary aspergillosis, tropical eosinophilia, bacterial endocarditis.
65
What immune complex-mediated complication occurs 1-2 weeks after recovery from meningococcal meningitis?
Polyarthritis and cutaneous vasculitis (immune complex-mediated). This should be differentiated from 'purpura fulminans' (which is acute DIC from endotoxin, occurring during acute infection, not after recovery).
66
How do you evaluate a patient with suspected post-infectious glomerulonephritis?
1) History of streptococcal sore throat (incubation 7-10 days) or scabies/skin infections (incubation 3-4 weeks). 2) Throat swab MCS for Group A Streptococcus. 3) Serum ASO (antistreptolysin O) and anti-DNAse B titers. 4) Serum C3 and circulating immune complex (CIC) levels. 5) Renal biopsy with immunofluorescence and histochemistry. 6) Screen for other infections: Hepatitis B, Salmonella, Schistosomiasis, etc.
67
What complement and immune complex findings are seen in post-streptococcal glomerulonephritis?
Low C3 + CIC positive. (C4 is usually normal – indicating alternative complement pathway activation.)
68
What complement and immune complex findings are seen in IgA nephropathy?
Normal C3 + CIC negative. (IgA nephropathy has normal complement levels and no circulating immune complexes – it is due to abnormal IgA deposition in the mesangium.)
69
What complement and immune complex findings are seen in SLE nephritis?
Low C3 + CIC positive. (SLE activates classical complement pathway, so both C3 and C4 are low.)
70
What complement and immune complex findings are seen in infective endocarditis (IE) with glomerulonephritis?
Low C4 + CIC positive. (C3 may be normal or low. Hypocomplementemia is due to classical pathway activation from immune complexes.)
71
What are the Duke's minor criteria for infective endocarditis that are immune complex-mediated?
Osler's nodes, glomerulonephritis, microscopic hematuria with red cell casts, Roth's spots, splinter hemorrhages, rheumatoid factor positivity.
72
What is Hyperreactive Malarial Splenomegaly (HMS) – formerly Tropical Splenomegaly Syndrome (TSS)?
A complication of chronic malaria (usually P. falciparum or P. vivax) characterized by massive splenomegaly (>10 cm), hepatomegaly, high serum IgM (>1000 iu/ml), high malarial antibody titers, hepatic sinusoidal lymphocytosis, and regression on prolonged antimalarial prophylaxis.
73
What is the immunological basis of Hyperreactive Malarial Splenomegaly (HMS/TSS)?
An imbalance in helper:suppressor T cells due to a decrease in suppressor T lymphocytes (CD8+ T cells), leading to overproduction of IgM by B cells. Treated patients show reversion toward normal T-cell subsets with chloroquine prophylaxis.
74
What are the cardinal features of Hyperreactive Malarial Syndrome (HMS/TSS)?
1) Enlarged spleen >10 cm (with hepatomegaly in most cases). 2) Regression of the syndrome on prolonged antimalarial prophylaxis (e.g., proguanil). 3) High malarial antibody titers in blood. 4) High serum IgM (usually >1000 iu/ml). 5) Hepatic sinusoidal lymphocytosis. 6) Evidence of hemolysis and hypersplenism with absolute lymphocytosis in peripheral blood.
75
What is the treatment for Hyperreactive Malarial Splenomegaly (HMS)?
Prolonged antimalarial prophylaxis (e.g., proguanil daily or weekly chloroquine phosphate) for 9-26 months or longer. Regression of splenomegaly and normalization of IgM levels confirms the diagnosis. Splenectomy is avoided due to risk of overwhelming post-splenectomy infection.
76
What is the case study diagnosis? A 52-year-old man with sore throat, fever, cough, no response to amoxicillin-clavulanic acid, develops hemolytic anemia (PCV 18%, MCV 113 fL – macrocytic), thrombocytopenia, and progressive right upper lobe consolidation.
Most likely diagnosis: Mycoplasma pneumoniae pneumonia (atypical pneumonia) with cold agglutinin-mediated hemolytic anemia (Type II immune hypersensitivity). The macrocytic anemia is due to reticulocytosis from hemolysis.
77
What organism is most likely in the case study (52M with progressive pneumonia, hemolytic anemia, no response to beta-lactam)?
Mycoplasma pneumoniae – does not have a cell wall, so beta-lactam antibiotics (amoxicillin-clavulanic acid) are ineffective. Causes cold agglutinin-mediated autoimmune hemolytic anemia (IgM antibodies against I antigen on RBCs, active at cold temperatures).
78
What type of immune hypersensitivity is cold agglutinin-mediated hemolytic anemia in Mycoplasma pneumonia?
Type II (Cytotoxic antibody hypersensitivity) – IgM antibodies bind to RBC surface antigens (I antigen), activate complement, and cause extravascular hemolysis (mainly in spleen and liver).
79
List 3 differential diagnoses for a patient with progressive pneumonia, hemolytic anemia, and thrombocytopenia.
1) Legionella pneumophila (Legionnaires' disease) – can cause hyponatremia, elevated LFTs, sometimes hemolysis. 2) Epstein-Barr virus (infectious mononucleosis) – causes atypical lymphocytosis, sometimes hemolytic anemia, and pulmonary infiltrates (rare). 3) Leptospirosis (Weil's disease) – causes pulmonary hemorrhage, hemolytic anemia, thrombocytopenia, and renal/liver involvement.
80
What investigations are required to confirm Mycoplasma pneumoniae infection?
1) Cold agglutinin titer (≥1:64 is supportive; >1:256 is highly suggestive). 2) Mycoplasma pneumoniae-specific IgM and IgG serology (paired acute/convalescent). 3) PCR of respiratory specimens (sputum, throat swab, BAL) – most sensitive. 4) Chest CT (shows bronchial wall thickening, centrilobular nodules, tree-in-bud opacities). 5) Consider cryoglobulins if vasculitis features present.
81
What is the treatment for Mycoplasma pneumoniae pneumonia with cold agglutinin hemolytic anemia?
1) Antibiotics: macrolides (azithromycin), doxycycline, or respiratory fluoroquinolones (levofloxacin, moxifloxacin). 2) Supportive care: keep patient warm to prevent cold agglutinin activation. 3) Severe hemolysis: corticosteroids (prednisone), IVIG, or rituximab (refractory cases). 4) Transfusion if severe anemia (use blood warmer).
82
What is the two-signal hypothesis for T-cell activation?
Signal 1 = TCR recognition of peptide-MHC complex. Signal 2 = co-stimulation (CD28 on T cell binding B7-1/B7-2 on APC). Without signal 2, T cells become anergic (tolerant).
83
What is the immunological mechanism of septic shock in Gram-negative bacterial infections?
Endotoxin (LPS) from Gram-negative bacteria stimulates macrophages to produce large amounts of TNF, IL-1, and IL-6. These cytokines cause vasodilation, increased capillary permeability, myocardial depression, and disseminated intravascular coagulation (DIC) – leading to distributive shock.
84
What is the role of superantigens in bacterial pathogenicity (e.g., S. aureus toxic shock syndrome)?
Superantigens (e.g., TSST-1, staphylococcal enterotoxins) bind directly to the Vβ region of TCR and MHC Class II outside the peptide-binding groove, activating 5-20% of all T cells (vs 0.001% for conventional antigens). This causes massive cytokine release ('cytokine storm') leading to fever, rash, hypotension, and multi-organ failure.
85
What is the difference between central and peripheral tolerance?
Central tolerance: deletion of self-reactive lymphocytes in the thymus (T cells) and bone marrow (B cells) during development. Peripheral tolerance: mechanisms that inactivate self-reactive lymphocytes that escape central tolerance – including anergy (lack of co-stimulation), Tregs, and deletion.
86
How does chronic inflammation from persistent infection lead to tissue damage?
Persistent antigen stimulation leads to chronic macrophage activation, continuous cytokine production (TNF, IL-1, TGF-β), and granuloma formation. This causes fibrosis, tissue destruction, and impaired organ function – as seen in tuberculosis, leprosy, and schistosomiasis.
87
What is the hygiene hypothesis?
The hypothesis that reduced exposure to infectious agents in early childhood (due to improved sanitation, antibiotics, vaccination) increases the risk of allergic and autoimmune diseases by skewing the immune system toward a Th2-dominant (allergic) phenotype.
88
What is the role of the complement system in immune complex clearance?
Complement (especially C3b) binds to immune complexes and facilitates their clearance by RBCs (via CR1 on erythrocytes) to the liver and spleen for removal. Deficiencies in early complement components (C1, C2, C4) are associated with SLE due to impaired immune complex clearance.
89
What is the difference between neutralizing antibodies and opsonizing antibodies?
Neutralizing antibodies bind to microbial surface structures (e.g., viral envelope proteins, bacterial toxins) and block their ability to infect cells or cause damage. Opsonizing antibodies (mainly IgG1, IgG3) bind to microbes and promote phagocytosis via Fc receptors on macrophages and neutrophils.
90
What is the role of Toll-like receptors (TLRs) in innate immunity?
TLRs are pattern recognition receptors (PRRs) on innate immune cells that recognize pathogen-associated molecular patterns (PAMPs). Examples: TLR4 recognizes LPS (Gram-negative bacteria), TLR2 recognizes lipoteichoic acid (Gram-positive bacteria), TLR3 recognizes dsRNA (viruses), TLR7/8 recognize ssRNA, TLR9 recognizes CpG DNA.
91
How do NK cells distinguish between healthy cells and infected/tumor cells?
NK cells are activated when they detect 'missing self' – loss of MHC Class I on infected/tumor cells (which would normally inhibit NK cells via KIR receptors). They also are activated by stress-induced ligands (MICA/MICB) and antibodies (ADCC – antibody-dependent cell-mediated cytotoxicity).
92
What is antibody-dependent cell-mediated cytotoxicity (ADCC)?
A process where NK cells (and other effectors) kill target cells coated with IgG antibodies. The NK cell's FcγRIII (CD16) binds the Fc portion of the antibody, triggering perforin/granzyme release and target cell apoptosis. Important for antiviral immunity and therapeutic monoclonal antibodies (e.g., rituximab).
93
What is the role of IL-10 in immune regulation?
IL-10 is an anti-inflammatory cytokine produced by regulatory T cells, macrophages, and some Th2 cells. It suppresses macrophage activation, inhibits pro-inflammatory cytokine production (TNF, IL-1, IL-6, IL-12), downregulates MHC Class II expression, and limits the extent of immune-mediated tissue damage.
94
What is the role of TGF-β in immune regulation?
TGF-β (transforming growth factor-beta) is a potent immunosuppressive cytokine produced by Tregs and many other cells. It inhibits T-cell proliferation, suppresses pro-inflammatory cytokine production, promotes IgA class switching in B cells, and is critical for the development and function of regulatory T cells (FoxP3+ Tregs).
95
What is the mechanism of action of checkpoint inhibitors in cancer immunotherapy?
Checkpoint inhibitors (e.g., anti-CTLA-4: ipilimumab; anti-PD-1: pembrolizumab, nivolumab) block inhibitory receptors on T cells, releasing the 'brakes' on T-cell activation. This enhances anti-tumor immune responses but can also cause immune-related adverse events (colitis, pneumonitis, dermatitis, endocrinopathies).
96
What is the role of CD40-CD40L interaction in immune responses?
CD40 on APCs (B cells, macrophages, DCs) binds CD40L (CD154) on activated CD4+ T cells. This interaction is critical for: 1) B-cell activation and class switching, 2) Macrophage activation (killing intracellular pathogens), 3) Dendritic cell maturation and IL-12 production. Hyper-IgM syndrome is caused by CD40L deficiency.
97
What is the pathophysiology of hyper-IgM syndrome?
X-linked recessive deficiency of CD40L (CD154) on T cells. Patients cannot undergo T-cell-dependent B-cell class switching (cannot switch from IgM to IgG, IgA, IgE). Presents with recurrent pyogenic infections (low IgG), Pneumocystis jirovecii pneumonia (low T-cell immunity), and neutropenia.
98
What is the difference between T-dependent and T-independent antigens?
T-dependent antigens (proteins) require CD4+ T cell help for B-cell activation, class switching, and memory formation. T-independent antigens (polysaccharides, lipopolysaccharides) can activate B cells without T cell help but produce only IgM, no memory, and are poorly immunogenic in infants.
99
What is the immunological mechanism of Rheumatic Fever (Type II hypersensitivity)?
Group A Streptococcus (M protein) has antigens that cross-react with human cardiac myosin, valve endothelium, and brain basal ganglia. Antibodies (IgG) bind to these tissues, causing inflammation and damage: carditis (pancarditis), arthritis, chorea (Sydenham's), erythema marginatum, and subcutaneous nodules.
100
What is the immunological mechanism of Guillain-Barré syndrome (GBS) after Campylobacter jejuni infection?
Molecular mimicry: C. jejuni lipooligosaccharide resembles GM1 ganglioside on peripheral nerves. Antibodies (IgG, IgM) cross-react with gangliosides, leading to complement-mediated demyelination (acute inflammatory demyelinating polyneuropathy – AIDP) or axonal damage (acute motor axonal neuropathy – AMAN).
101
What is the role of PD-1 and its ligands (PD-L1/PD-L2) in immune regulation?
PD-1 (programmed cell death protein 1) is an inhibitory receptor on activated T cells. Its ligands PD-L1/PD-L2 are expressed on APCs, tumor cells, and inflamed tissues. PD-1/PD-L1 engagement inhibits T-cell activation, promotes T-cell exhaustion in chronic infections, and protects tissues from immune-mediated damage.
102
What is the difference between T-cell exhaustion and anergy?
T-cell exhaustion: occurs in chronic infections (e.g., HIV, HBV, HCV) with persistent antigen stimulation – T cells progressively lose effector functions (IL-2 → TNF → IFNγ → cytotoxicity) and express inhibitory receptors (PD-1, CTLA-4, TIM-3, LAG-3). Anergy: occurs when T cells receive signal 1 (TCR) without signal 2 (co-stimulation) – they are alive but functionally unresponsive and do not proliferate or produce IL-2.
103
What is the immunological mechanism of granuloma formation in tuberculosis?
Persistent mycobacterial antigens trigger a Th1-mediated delayed-type hypersensitivity (Type IV) response. Macrophages are activated by IFNγ and attempt to contain the bacteria, forming a granuloma with epithelioid cells, Langhans giant cells, and a rim of lymphocytes and fibrosis. Central caseous necrosis occurs from macrophage death and tissue destruction.
104
What is the role of IL-17 in immunity to extracellular bacteria and fungi?
IL-17 (produced by Th17 cells) recruits neutrophils to sites of infection by inducing chemokine (CXCL1, CXCL8) and G-CSF production. It is critical for defense against extracellular bacteria (Klebsiella, S. aureus, E. coli) and fungi (Candida albicans). Defects in Th17 immunity (e.g., STAT3 mutations, AIRE deficiency) cause chronic mucocutaneous candidiasis.
105
What is the immunological mechanism of leprosy spectrum (tuberculoid vs lepromatous)?
Tuberculoid leprosy: strong Th1 response (IFNγ, IL-2) – few bacteria, well-formed granulomas, limited disease, but nerve damage from inflammation. Lepromatous leprosy: weak Th1 response, strong Th2/regulatory response (IL-4, IL-10, TGF-β) – uncontrolled bacterial growth, diffuse disease, multiple lesions, but less inflammation. Borderline forms have mixed responses.
106
What is the role of PAMP recognition by the immune system?
PAMPs (Pathogen-Associated Molecular Patterns) are conserved microbial molecules recognized by PRRs (Pattern Recognition Receptors) like TLRs, NLRs, RLRs. This triggers innate immune activation: inflammation, phagocytosis, cytokine production, and induction of adaptive immunity. Examples: LPS (TLR4), flagellin (TLR5), dsRNA (TLR3), peptidoglycan (NOD2).
107
What is the immunological mechanism of hemolytic uremic syndrome (HUS) after E. coli O157:H7 infection?
Shiga toxin damages vascular endothelium (especially in kidney and brain), leading to endothelial activation, platelet aggregation, and microthrombi formation. This causes microangiopathic hemolytic anemia (fragmented RBCs), thrombocytopenia, and renal failure. Complement dysregulation (alternative pathway) exacerbates the disease.
108
What is the difference between active and passive immunity?
Active immunity: host produces its own antibodies and memory cells after exposure to antigen (infection or vaccination) – long-lasting. Passive immunity: transfer of pre-formed antibodies (maternal IgG to fetus, breast milk IgA, immune globulin therapy) – immediate but short-lived (weeks to months).
109
What is the role of the complement system in enhancing antibody responses?
Complement (especially C3d) binds to immune complexes and microbes. C3d engages CR2 (CD21) on B cells, which co-ligates with the B-cell receptor (BCR) and CD19, lowering the threshold for B-cell activation by 100-1000-fold. This enhances humoral immunity and immunological memory.
110
What is the mechanism of immune evasion by Trypanosoma brucei (African trypanosomiasis)?
Antigenic variation via the VSG (variant surface glycoprotein) coat. The parasite has hundreds of VSG genes, but only expresses one at a time. The host makes antibodies against the expressed VSG, clearing that variant, but a small population switches VSG expression, escaping the immune response – causing waves of parasitemia and chronic infection.
111
What is the immunological mechanism of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)?
Antibody-dependent enhancement (ADE): pre-existing non-neutralizing or sub-neutralizing antibodies from a prior dengue infection (different serotype) bind to the virus but do not neutralize it. The antibody-virus complex enters Fc receptor-bearing cells (monocytes/macrophages) more efficiently, increasing viral replication, cytokine production (TNF, IL-6, IL-8), and vascular permeability – leading to plasma leak and shock.
Internal Medicine
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