IMMUNOLOGY CHAPTER 6

Question 1

Epithelial Barriers
❓ What is their role in innate immunity?

Answer 1

First line of defense – block entry of microbes.

Key Features:

Found in skin, GI, and respiratory tracts.

Produce antimicrobial molecules like defensins.

Contain lymphocytes that fight microbes at entry sites.

Question 2

Phagocytes: Neutrophils & Macrophages
❓ What do they do?

Answer 2

Circulating monocytes become macrophages in tissue.

Some macrophages are tissue-resident (e.g., Kupffer cells, microglia, alveolar macrophages).

Major players in chronic inflammation

Question 3

Dendritic Cells (DCs)
❓ What’s their main job?

Answer 3

Act as antigen-presenting cells & danger detectors.

Functions:

Capture antigens → present to T cells.

Sense microbes & damage → release cytokines.

Crucial for initiating innate immune responses.

Question 4

Innate Lymphoid Cells (ILCs)
❓ What are they and what do they do?

Answer 4

Tissue-resident lymphocytes activated by cytokines.

Groups & Functions:

Don’t respond to antigens (no TCRs).

Produce cytokines like Th1, Th2, Th17 cells.

Group 1 ILCs = NK cells: destroy virally infected or transformed cells.

Question 5

Which other cells participate in innate immunity?

Answer 5

Mast cells, epithelial cells, and endothelial cells.

Mast Cells:
Release histamine, cytokines, and other inflammatory mediators.

Question 5

Which plasma proteins help in innate immunity?

Answer 5

Complement system, mannose-binding lectin, C-reactive protein, lung surfactant.
Functions:
Complement proteins: destroy microbes via lysis, opsonization, or recruitment.
MBL & CRP: bind microbes and enhance phagocytosis.
Surfactant: protects against inhaled pathogens.

Question 6

What are the components of innate immunity?

Answer 6

1- epithelial cells
2- phagocytes
3- innate lymphoid cells
4- dendritic cells
5- soluble proteins
6- other sentinel cells like mast, epithelial and endothelial cells

Question 7

What do innate immune cells recognize?

Answer 7

✅ Pathogen-Associated Molecular Patterns (PAMPs) – structures shared by microbes.
✅ Damage-Associated Molecular Patterns (DAMPs) – released from injured/necrotic cells.

Question 7

which type of immunity do complement system activation follow

Answer 7

Lectin pathway and alternative –> innate
classic pathway –> adaptive

Question 7

What are PRRs and where are they found?

Answer 7

✅ Cellular receptors that recognize PAMPs and DAMPs.
Locations:

Plasma membrane – detect extracellular microbes.

Endosomes – detect ingested microbes.

Cytosol – detect intracellular microbes.

Question 8

What are TLRs and what do they do?

Answer 8

✅ PRRs that recognize various microbial components.
Locations: Plasma membrane & endosomes.
Pathway activated:

NF-κB → cytokines + adhesion molecules.

IRFs → type I interferons (antiviral response).
Note: Mutations → immunodeficiencies.

Question 8

What do NLRs detect?

Answer 8

✅ Cytosolic PRRs that sense:
Necrotic cell products (e.g., ATP, uric acid).
Intracellular K+ loss.
Microbial products.
Key pathway:
Activate inflammasome → activates caspase-1 → cleaves pro–IL-1 → active IL-1 (inflammatory).

Associated disorders:
autoinflammatory syndromes ( gain of function mutation in NLR and loss of fucntion mutation in regulators of inflammasome )
, gout (urate crystales)
, diabetes type 2 ( lipids )
, atherosclerosis. ( cholesterol crystals)

Question 8

What do CLRs recognize?

Answer 8

✅ Detect fungal glycans on fungi.
📍 Found on macrophages & dendritic cells.
➡️ Trigger inflammation against fungi.

Question 9

What do RLRs detect?

Answer 9

✅ Detect viral RNA in the cytosol.
➡️ Trigger antiviral cytokines.

Question 9

Cytosolic DNA Sensors & STING Pathway

Answer 9

✅ Recognize microbial DNA (often viral).
➡️ Activate STING pathway → interferon-α production.
🚨 Overactivation → interferonopathies.

Question 9

What do leukocyte GPCRs detect?

Answer 9

✅ Detect N-formylmethionyl peptides → chemotaxis toward bacteria.
💡 Bacteria use N-formylmethionine to start protein synthesis; host cells rarely do.

Question 9

What sugars do mannose receptors recognize?

Answer 9

✅ Detect microbial sugars with terminal mannose residues.
➡️ Trigger phagocytosis of microbes.

Question 9

What is the primary function of natural killer (NK) cells in innate immunity?

Answer 9

NK cells recognize and destroy severely stressed or abnormal cells, such as virus-infected or tumor cells.

Question 10

How is the killing activity of NK cells regulated?

Answer 10

NK cell cytotoxicity is regulated by activating receptors (recognize stress-induced ligands) and inhibitory receptors (recognize self class I MHC molecules).

Question 10

What is antibody-dependent cellular cytotoxicity (ADCC), and how is it related to NK cells?

Answer 10

ADCC is the process by which NK cells lyse IgG-coated target cells via their CD16 receptor.

Question 10

What percentage of peripheral blood lymphocytes do NK cells make up, and what surface receptor do they express?

Answer 10

NK cells make up ~5–10% of peripheral blood lymphocytes and express CD16, a receptor for the Fc tail of IgG.

Question 11

Why do NK cells preferentially kill virus-infected or tumor cells?

Answer 11

Infected/tumor cells often have upregulated activating ligands and downregulated class I MHC, tipping the balance toward NK cell activation and killing.

Question 12

What cytokine do NK cells secrete, and what is its function?

Answer 12

NK cells secrete interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes—providing early defense against intracellular pathogens.

Question 13

What are the two major defense mechanisms of the innate immune system?

Answer 13

Inflammation – driven by cytokines, complement products, and mediators that recruit leukocytes to destroy microbes and damaged cells.

Antiviral defense – mediated by type I interferons and NK cells.

Question 13

Which cytokines regulate NK cell activity, and what are their roles?

Answer 13

IL-2 & IL-15 stimulate NK cell proliferation. IL-12 enhances killing activity and IFN-γ secretion by NK cells.

Question 14

How do type I interferons contribute to antiviral defense in innate immunity?

Answer 14

Type I interferons induce an antiviral state by activating enzymes that degrade viral nucleic acids and inhibit viral replication in infected and neighboring cells.

Question 14

How does innate immunity interact with adaptive immunity?

Answer 14

Innate immunity provides danger signals that stimulate and shape the adaptive immune response, ensuring a stronger and specific reaction.

Question 15

What are the primary cells of the adaptive immune system and their key features?

Answer 15

👨‍⚕️ T lymphocytes (T cells): Thymus-derived, responsible for cellular immunity 🧪 B lymphocytes (B cells): Bone marrow–derived, responsible for humoral immunity 🧬 Both have highly specific antigen receptors 🔁 Lymphocytes circulate via blood & lymphatics ➜ immune surveillance 🕵️‍♂️ They localize in lymphoid organs but only interact when stimulated by antigens

Question 15

What are the two types of adaptive immunity, and what do they protect against?

Answer 15

💉 Humoral immunity: Mediated by B lymphocytes and their secreted antibodies (immunoglobulins, Ig) Protects against extracellular microbes and their toxins 🧬 Cell-mediated (cellular) immunity: Mediated by T lymphocytes Defends against intracellular microbes (e.g., viruses) and cancer cells

Question 16

What is the significance of antigen receptor gene recombination in lymphocyte diversity?

Answer 16

🔀 Somatic recombination of gene segments during lymphocyte maturation (in thymus for T cells, bone marrow for B cells) 🧬 Creates diverse antigen receptors, especially in antigen-binding regions 🛠️ Mediated by RAG-1 and RAG-2 enzymes ❌ Mutations in RAG = failure to generate mature lymphocytes

Question 17

What are the three major populations of T cells and their primary functions?

Answer 17

🧪 Helper T cells (CD4+): Stimulate B cells to produce antibodies & activate phagocytes 🔪 Cytotoxic T cells (CD8+): Kill infected or abnormal cells 🛑 Regulatory T cells: Suppress immune responses & prevent autoimmunity

Question 17

What is clonal selection in adaptive immunity?

Answer 17

🔬 Clonal selection: When antigen appears, it activates pre-existing specific lymphocytes 👯‍♂️ A clone = group of lymphocytes with identical receptors specific to one antigen

Question 18

What is the TCR complex composed of, and what does it do?

Answer 18

TCR is linked with CD3 complex + ζ (zeta) chain dimer These are invariant and help transduce signals into the T cell upon antigen binding

Question 18

What are γδ T cells and their characteristics?

Answer 18

Express γ and δ chains instead of αβ Recognize peptides, lipids, small molecules without MHC presentation Aggregate in epithelial surfaces (skin, GI, urogenital tract) Function is not fully established

Question 18

What is the structure and function of the T-cell receptor (TCR)?

Answer 18

Composed of disulfide-linked α and β chains (in 95% of T cells) Each chain has variable (antigen-binding) and constant regions Recognizes peptide antigens presented by MHC molecules on APCs This is known as MHC restriction

Question 19

Where do T lymphocytes develop and where are they found?

Answer 19

🏗️ Develop: In thymus from hematopoietic stem cells (HSCs) 🌊 Found: In blood (60–70% of lymphocytes) and T-cell zones of secondary lymphoid organs

Question 19

What other surface proteins do T cells express and what are their functions?

Answer 19

CD4 (on helper T cells): Binds to Class II MHC CD8 (on cytotoxic T cells): Binds to Class I MHC CD28: Provides costimulatory signals during activation Integrins: Promote adhesion to APCs

Question 19

Who are NK-T cells and what do they recognize?

Answer 19

Express markers of both T cells and NK cells Have limited TCR diversity Recognize glycolipids presented by CD1 (MHC-like molecule) Functions are not well defined

Question 20

How does MHC restriction affect CD4+ and CD8+ T cell recognition?

Answer 20

CD4+ T cells recognize antigens on Class II MHC CD8+ T cells recognize antigens on Class I MHC CD4/CD8 act as coreceptors, necessary for T cell activation

Question 20

What is the function of B lymphocytes in adaptive immunity?

Answer 20

🎯 Only cells that can produce antibodies (humoral immunity) 🧫 Recognize antigens via B-cell receptor (BCR) complex 🔁 After activation: Become plasma cells 🏭 (antibody factories) Or memory B cells 🧠 (long-lived and rapid responders)

Question 21

Where do B cells develop and where are they found?

Answer 21

Develop in the bone marrow 🌐 Found in: Blood (10–20% of lymphocytes) Peripheral lymphoid tissues: lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT)

Question 22

What molecules make up the BCR complex?

Answer 22

Membrane-bound IgM and IgD (antigen recognition) Igα (CD79a) & Igβ (CD79b): 🧬 invariant proteins for signal transduction Function like CD3/ζ in T cells

Question 23

What other key receptors do B cells express and what are their roles?

Answer 23

CR2 (CD21): Binds complement products 🧫 Entry point for Epstein-Barr virus (EBV) 🦠 CD40: Receives signals from helper T cells

Question 23

What is the primary role of dendritic cells in the immune system?

Answer 23

Present protein antigens via MHC to naïve T cells

Question 23

What features make dendritic cells effective APCs?

Answer 23

📍 Strategic location: under epithelia and in tissues 🧬 Express TLRs & lectins to detect microbes 🧲 Migrate to T-cell zones in lymphoid organs 🧠 Express high levels of MHC + costimulatory molecules

Question 24

What are Langerhans cells?

Answer 24

🧴 Immature dendritic cells found in the epidermis

Question 25

Q: What are follicular dendritic cells (FDCs) and what do they do?

Answer 25

Found in germinal centers of lymphoid follicles Bear Fc receptors (for IgG) & C3b receptors Trap antigen–antibody or antigen–complement complexes 🎯 Help B cells select high-affinity antibodies

Question 26

What are the two main types of immune system tissues?

Answer 26

Primary (Generative/Central) Lymphoid Organs Where T & B cells mature and become antigen-responsive Secondary (Peripheral) Lymphoid Organs Where adaptive immune responses are initiated

Question 26

What are the 3 major roles of macrophages in adaptive immunity?

Answer 26

🎯 APCs: Present processed peptides to T cells 🔥 Effector cells: Activated by T cells to kill intracellular microbes 🧽 Phagocytosis: Ingest microbes opsonized by IgG or C3b

Question 27

What are the two principal primary lymphoid organs?

Answer 27

Thymus 🫀: T-cell development Bone marrow 🦴: Generation of all blood cells including naïve B cells

Question 28

Where are B and T cells located within lymph nodes and spleen?

Answer 28

Lymph nodes: B cells: In follicles (outer cortex) May form germinal centers after activation T cells: In paracortex Site of interaction with DCs Spleen: T cells: In periarteriolar lymphoid sheaths (PALS) B cells: In follicles of white pulp

Question 28

What are the major secondary lymphoid organs and their roles?

Answer 28

1- Lymph nodes: Filter lymph-borne antigens Site of most adaptive immune responses Antigens from tissues are delivered here by DCs via lymphatics 2- Spleen: Filters blood-borne antigens Contains sinusoids lined with DCs & macrophages 3- Cutaneous & Mucosal Lymphoid Tissues: Located under epithelia of skin, GI, and respiratory tracts Examples: Peyer patches (intestine), tonsils Rich in memory lymphocytes

Question 29

MHC Function & Types

Answer 29

MHC molecules display peptide fragments to T cells, critical for antigen recognition and T cell activation. 🔑 Two main types: Class I MHC: on all nucleated cells & platelets 🧫 → presents cytoplasmic antigens (e.g., viruses) to CD8+ T cells. Class II MHC: on APCs only (DCs, macrophages, B cells) 🌐 → presents extracellular antigens to CD4+ T cells.

Question 29

Why do lymphocytes recirculate, and how does it differ by cell type?

Answer 29

Naïve T cells: Constantly circulate to secondary lymphoid organs in search of antigen Effector T cells: Migrate to infection sites to fight microbes Plasma cells: 🛌 Stay in lymphoid tissues or bone marrow and release antibodies into circulation

Question 30

MHC Genetics & Polymorphism

Answer 30

🧬 MHC = HLA system on chromosome 6 🎲 Highly polymorphic → thousands of alleles → major transplant barrier 👨‍👩‍👧 HLA alleles inherited as haplotypes (1 from each parent); siblings have 25% chance of matching 🧬 Ensures species-wide ability to respond to diverse pathogens ⚠️ Also explains autoimmune risk (e.g., HLA-B27 → ankylosing spondylitis)

Question 30

MHC Class II: Structure & Function

Answer 30

🧩 Structure: polymorphic α + β chains (HLA-DP, DQ, DR) 📦 Binds peptides in α1–β1 cleft 🧃 Presents peptides from endocytosed extracellular antigens (processed in lysosomes) 🧠 Recognized by CD4+ helper T cells → supports B cell antibody production & macrophage activation 🧬 CD4 binds to β2 domain → MHC-II restricted

Question 31

MHC Class I: Structure & Function

Answer 31

📍 Structure: polymorphic α chain (HLA-A, B, C) + β2-microglobulin 🎯 Binds peptides in α1–α2 groove 📦 Loads peptides from proteasome-processed cytosolic proteins in the ER 🧠 Recognized by CD8+ cytotoxic T cells ⚔️ Key for killing virus-infected or tumor cells 🧬 CD8 binds to α3 domain → MHC-I restricted recognition

Question 31

Clinical Relevance of MHC

Answer 31

Immune segregation: Class I → cytoplasmic microbes/tumors → CTL response 💥 Class II → extracellular/phagocytosed microbes → helper T response 🛡️ 🔁 Only peptides that bind MHC are immunogenic 🌼 HLA types affect disease risk (e.g., allergies, infections, autoimmunity) 🚨 Transplants fail if HLA not matched → MHC drives rejection

Question 32

Cytokines: Key Immune Messengers

Answer 32

Secreted proteins that regulate immune cell activity 💬 Called interleukins (ILs) if they mediate communication between leukocytes 📍 Act autocrine (same cell) or paracrine (nearby) – rarely endocrine

Question 33

nnate Immunity Cytokines

Answer 33

💥 Rapidly released after microbe detection 🛡️ Induce inflammation + inhibit viral replication 💡 Key cytokines: TNF, IL-1, IL-12 Type I IFNs (IFN-α, IFN-β) IFN-γ (also bridges to adaptive) Chemokines 🚦 (cell movement) 🔬 Produced by: Macrophages, DCs, NK cells, ILCs, endothelium, epithelium

Question 33

Adaptive Immunity Cytokines

Answer 33

🎯 Mainly made by activated CD4+ T cells 📈 Stimulate: T cell proliferation/differentiation Effector cell activation 🌟 Key cytokines: IL-2: T cell growth IL-4, IL-5: B cell help, eosinophils IL-17: neutrophil recruitment IFN-γ: macrophage activation 🧘‍♂️ Regulatory cytokines: IL-10, TGF-β (suppress inflammation)

Question 33

Cytokines for Hematopoiesis

Answer 33

🧬 Called Colony-Stimulating Factors (CSFs) 🧠 Stimulate bone marrow to increase leukocyte production 🔄 Replace cells lost during immune responses Examples: GM-CSF IL-3 📍 Source: marrow stromal cells, T cells, macrophages

Question 34

Therapeutic Use of Cytokines

Answer 34

🛑 Cytokine inhibitors (e.g., anti-TNF) treat autoimmune/inflammatory diseases like RA 🚀 Cytokine therapy boosts immunity or mobilizes stem cells for transplantation 📦 Example: G-CSF → moves stem cells into blood for collection

Question 35

B Cell Activation & Antibody Production

Answer 35

T-dependent responses (proteins): BCR binds antigen → endocytosis → MHC II display Helper T cell (CD4+) binds MHC II + CD40L → secretes cytokines ➕ Leads to: Isotype switching (IgM → IgG, IgA, IgE) Affinity maturation 🧪 T-independent responses (polysaccharides/lipids): No T cell help (can't bind MHC) Repetitive epitopes crosslink BCRs Mainly IgM response (less varied, lower affinity)

Question 35

Germinal Centers what happens inside of it

Answer 35

Location of: 🧪 Isotype switching 🎯 Affinity maturation (better antigen-binding) 🧑‍🏫 Helped by T follicular helper (TFH) cells 🔄 Activated B cells → plasma cells + memory B cells

Question 36

Antibody Functions by Class

Answer 36

IgG: ⚔️ Opsonization → phagocytosis 🎯 Activates complement (classical path) 👶 Crosses placenta → newborn immunity IgM: 🧪 First antibody made, strong complement activator IgA: 🫁🦠 Secreted at mucosa → neutralizes microbes in GI/resp tract IgE: 🪱 Binds eosinophils → parasite destruction (helminths) 🔁 Driven by IL-4, IL-5 (from Th2)

Question 37

Decline of Immune Responses

Answer 37

Most effector lymphocytes die by apoptosis after infection clears Prevents overactive immune response 💤 Immune system returns to resting state

Question 37

function of plasma cells

Answer 37

🧬 Each plasma cell makes antibodies against same antigen as initial BCR 🏡 Some migrate to bone marrow → live months to years 🔄 Continue antibody production long after infection

Question 37

Immunologic Memory

Answer 37

👥 Memory cells = expanded pool of antigen-specific lymphocytes ⚡ Faster + more effective on reexposure than naïve cells

Question 38

Hypersensitivity Overview

Answer 38

💥 Definition: Injurious immune response to antigen in sensitized individuals 🔁 Can be triggered by: 🌿 Exogenous antigens (e.g. pollen, food, drugs, microbes) 🧬 Endogenous antigens (self → autoimmune disease) 🧪 Results from: 🚨 Imbalance between effector vs regulatory immune responses 🧬 Often linked to HLA/non-HLA gene variants

Question 38

Hypersensitivity 1

Answer 38

Type I – Immediate Hypersensitivity (Allergy, Anaphylaxis) 🤝 Trigger: Allergen binds IgE on mast cells (sensitized by prior exposure) ⛓ Mediators: Th2 cells, IgE, mast cells, eosinophils ⏱ Timing: Seconds to minutes 💣 Mast cell release: histamine, leukotrienes, prostaglandins → vasodilation, bronchospasm, inflammation 🧫 Example: Anaphylaxis, asthma, hay fever, urticaria (hives)

Question 39

Hypersensitivity Type IV – T Cell–Mediated (Delayed-Type)

Answer 39

⏱ Timing: 24–72 hours 🧠 Mediators: Th1 cells → IFN-γ → macrophage activation Th17 cells → IL-17 → neutrophilic inflammation CD8+ CTLs → direct cell killing 🧫 Example: Contact dermatitis (e.g. poison ivy) Type 1 diabetes Tuberculosis (granulomas) MS, RA, Crohn disease

Question 39

Hypersensitivity Type II – Antibody-Mediated Cytotoxicity

Answer 39

🎯 Trigger: IgG or IgM binds antigen on cells/tissues ⚙️ Mechanisms: 🧹 Opsonization → phagocytosis (Fc/C3b receptors) 💥 Complement-mediated lysis 🔄 Antibody interference with receptors 🧫 Example: Autoimmune hemolytic anemia Goodpasture syndrome Myasthenia gravis (receptor blockade) Graves disease (receptor stimulation)

Question 40

Hypersensitivity Type III – Immune Complex–Mediated

Answer 40

🧬 IgG or IgM + soluble antigen → immune complex 🧷 Complex deposits in tissues → complement activation → neutrophil recruitment 🔬 Neutrophils release enzymes + ROS → tissue injury ⏱ Timing: Hours to days 🧫 Example: Systemic lupus erythematosus (SLE) Post-streptococcal glomerulonephritis Serum sickness, arthus reaction

Question 40

Systemic vs. Local Reactions in HS1

Answer 40

🩸 Systemic: * Often triggered by injection or ingestion of antigen * Can cause anaphylaxis and shock (life-threatening) 🌿 Local: * Depends on entry route of allergen * Includes: Urticaria (hives), eczema Allergic rhinitis (hay fever), conjunctivitis Bronchial asthma Allergic gastroenteritis (food allergy)

Question 41

What are the 2 phases of Type I hypersensitivity?

Answer 41

Immediate phase (within minutes): Vasodilation 🩸 Vascular leakage 💧 Smooth muscle spasm 💨 Gland secretion (e.g., mucus) Late-phase (2–24 hrs later): Infiltration by: * Eosinophils, neutrophils, basophils, monocytes, CD4+ T cells Causes mucosal epithelial damage 🧱

Question 41

What causes most immediate hypersensitivity disorders?

Answer 41

🔸 Excessive Th2 responses 🔸 Th2 cells: Stimulate IgE production Promote inflammation

Question 42

What is the role of Th2 cells in HS1

Answer 42

Antigen presented to naive CD4+ T cells (via DCs) Differentiate into Th2 cells under influence of IL-4 On re-exposure to antigen, Th2 cells secrete: IL-4: promotes IgE switching & more Th2 IL-5: activates eosinophils IL-13: enhances IgE, mucus secretion 🧲 Also release chemokines that recruit more Th2 cells & leukocytes

Question 42

Th2-High vs Th2-Low in atopic disease

Answer 42

🫁 Seen in chronic asthma, dermatitis 🔹 Th2-high: Strong Th2 cytokine signature 🔹 Th2-low: Weaker response 🧪 Therapy tip: IL-4/IL-5 antagonists work best in Th2-high patients

Question 43

What are type 2 ILCs?

Answer 43

🔹 Innate Lymphoid Cells (ILC2s) in tissues 🔹 Activated by cytokines from damaged epithelium 🔹 Secrete IL-5 and IL-13 🔹 Contribute to early inflammation before Th2 dominance

Question 44

What are mast cells and why are they important?

Answer 44

🧬 Bone marrow–derived immune cells 📍 Found in tissues, especially near: Small blood vessels Nerves Subepithelial areas (common allergy sites) 🧪 Contain cytoplasmic granules loaded with: Biologically active mediators Acidic proteoglycans (bind dyes like toluidine blue) 📚 ("Mast" = old German term for feeding; based on mistaken belief their granules fed nearby tissue)

Question 45

How are mast cells activated?

Answer 45

🔸 They express high-affinity FcεRI receptors for IgE 🔸 After first exposure, IgE binds these receptors = "sensitization" 🔸 On re-exposure, multivalent antigen cross-links adjacent IgEs 🔸 Triggers signaling cascade → degranulation & mediator release 📌 Results in: Immediate allergic symptoms Initiation of late-phase inflammation 🔸 Complement fragments: C3a, C5a = anaphylatoxins Bind mast cell receptors → histamine release 🔸 Other triggers include: IL-8 (chemokine) Drugs (e.g., morphine, codeine) Bee venom (melittin) Adenosine Physical stimuli (heat, cold, sunlight)

Question 45

What happens when a sensitized mast cell meets its antigen again?

Answer 45

1-Antigen binds surface IgE 2-Cross-links adjacent IgEs 3-Triggers FcεRI signal → Release of preformed granules Synthesis of new mediators

Question 45

What are the 3 main types of mediators released by mast cells?

Answer 45

Preformed granule contents Lipid-derived mediators Cytokines 🧠 These mediators drive both the immediate reaction (minutes) and late-phase reaction (2–24 hrs).

Question 46

Granule Contents of mast cell

Answer 46

1. Vasoactive amines 🧪 🔹 Histamine (most important): 🫁 Smooth muscle contraction 🩸 ↑ Vascular permeability 🤧 ↑ Mucus secretion (nasal, bronchial, gastric) 2. Enzymes 🔧 🔹 Neutral proteases: Tryptase, chymase 🔹 Acid hydrolases 📌 Function: ⚠️ Tissue damage 🧬 Generate kinins and complement fragments (e.g., C3a) 3. Proteoglycans 🧫 🔸 Heparin (anticoagulant) 🔸 Chondroitin sulfate 📦 Help package and store granule contents

Question 46

What enzyme triggers lipid mediator synthesis in HS1?

Answer 46

Phospholipase A2 → liberates arachidonic acid

Question 47

Leukotrienes, prostaglandins and PAF function in HS1

Answer 47

🧨 Leukotrienes (via 5-lipoxygenase): C4 & D4: 🚨 Potent vasodilators & bronchoconstrictors ⚡️ 1000x more active than histamine B4: 🎯 Chemoattractant for neutrophils, eosinophils, monocytes 💨 Prostaglandin D2 (via cyclooxygenase): Most abundant in mast cells 🫁 Bronchospasm, 🤧 ↑ Mucus secretion 🧷 Platelet-Activating Factor (PAF): 📍 Causes: Platelet aggregation Bronchospasm Histamine release Vasodilation & vascular leak

Question 47

Cytokines from Mast Cells

Answer 47

Key cytokines & actions: TNF, IL-1, chemokines → recruit leukocytes (esp. in late phase) IL-4 → promotes Th2 response & IgE switching 🔄 Recruited cells release more cytokines, driving inflammation 📍 Epithelial cells also produce chemokines, contributing to the response

Question 48

Which cells dominate the late-phase?

Answer 48

Eosinophils 🧪 (most prominent) Also: neutrophils, basophils, monocytes, CD4+ T cells

Question 49

Eosinophils – key features: in HS1

Answer 49

Recruited by: Eotaxin (from epithelial cells, Th2, mast cells) IL-5 (most potent eosinophil activator) Release: Proteolytic enzymes Major Basic Protein (MBP) Eosinophil Cationic Protein (ECP) 🧱 Cause epithelial damage and sustain inflammation

Question 49

What are Charcot-Leyden crystals?

Answer 49

Composed of galectin-10 Found in asthma sputum 🔁 Promote inflammation & enhance Th2 responses

Question 49

What genes are linked to allergic disease in atopic individuals?

Answer 49

IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF 📍 Also associated with certain HLA alleles on chromosome 6

Question 49

How do environmental factors influence allergy risk?

Answer 49

Air pollutants in urban/industrial areas ↑ allergy risk Viral airway infections (esp. in childhood) → can trigger asthma

Question 49

What are nonatopic allergies?

Answer 49

➡️ Immediate hypersensitivity without Th2 or IgE involvement ⚠️ Triggered by non-antigenic stimuli: 🌡️ Temperature extremes 🏃‍♂️ Exercise 📌 Caused by abnormal mast cell activation 🧠 ~20–30% of immediate reactions are nonatopic

Question 49

What is systemic anaphylaxis

Answer 49

➡️ Severe, rapid-onset Type I hypersensitivity reaction Symptoms: 🔻 Vascular shock 💦 Widespread edema 😮‍💨 Respiratory distress 🫁 Bronchoconstriction 🔊 Hoarseness (due to laryngeal edema) 🤢 GI symptoms (vomiting, cramps, diarrhea) 💀 Can be fatal in <1 hour

Question 49

What are localized Type I allergic conditions?

Answer 49

➡️ Affect ~10–20% of population Common allergens: Pollen, dander, dust mites, foods 🩺 Includes: 🌼 Allergic rhinitis (hay fever) 🫁 Bronchial asthma 🌊 Urticaria (hives) 👶 Atopic dermatitis 🍤 Food allergies

Question 49

What is the basic mechanism of Type II hypersensitivity

Answer 49

💥 IgG or IgM antibodies bind to antigens on cell surfaces or extracellular matrix → lead to: Cell destruction via opsonization/phagocytosis or ADCC Inflammation Cellular dysfunction without cell death

Question 50

Opsonization & Phagocytosis in HS2

Answer 50

IgG binds to cell antigens ➡ Fc receptors on phagocytes recognize them 🧲 IgG or IgM can activate complement ➡ C3b/C4b opsonins deposited Phagocytes bind C3b/C4b → phagocytosis & cell destruction Complement can also form the membrane attack complex (MAC) ➡ osmotic lysis of thin-walled cells

Question 50

What are clinical situations where antibody-mediated cell destruction occurs in HS2

Answer 50

💉 Transfusion reaction – preformed antibodies destroy mismatched donor RBCs 👶 Erythroblastosis fetalis – maternal anti-Rh IgG crosses placenta and destroys fetal RBCs 🔬 Autoimmune cytopenias – autoantibodies destroy RBCs, WBCs, or platelets (e.g., autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia) 💊 Drug-induced hemolysis – drug binds to RBC membrane → becomes immunogenic → antibody response

Question 50

How do antibodies cause inflammation in tissues in HS2

Answer 50

Antibodies deposit in tissues (e.g., basement membranes) 🧱 Activate complement → C5a = chemotaxis, C3a/C5a = ↑ vascular permeability Recruited neutrophils/monocytes release: Lysosomal enzymes (proteases digest collagen, elastin, etc.) Reactive oxygen species (ROS) 🧪 → tissue damage

Question 51

What is an example of Type II hypersensitivity causing dysfunction without cell destruction

Answer 51

⚡ Myasthenia gravis: Autoantibodies block acetylcholine receptors at neuromuscular junction → muscle weakness 🔥 Graves disease: Autoantibodies stimulate TSH receptor → hyperthyroidism

Question 51

What is Type III Hypersensitivity?

Answer 51

🧪 Definition: Immune complex–mediated tissue injury 🧬 Mechanism: Antigen-antibody (Ag-Ab) complexes form in circulation and deposit in tissues, triggering inflammation and tissue damage

Question 51

What are common deposition sites and why?

Answer 51

Preferred sites: Glomeruli (kidney) Joints Small vessels 🌀 Reason: Blood filtration & high-pressure flow → concentration of immune complexes

Question 51

What are the 3 phases of systemic immune complex disease (HS3)

Answer 51

1️⃣ Immune Complex Formation: 💉 Antigen injected → Ab formed ~1 week later 🧬 Ag-Ab complexes circulate 2️⃣ Complex Deposition: 🏗 Medium-sized complexes, slight antigen excess = most pathogenic 🔁 Deposit in glomeruli, synovium, vessels 3️⃣ Inflammation & Injury: 🔥 Complement activation (C3a, C5a) 🧲 Neutrophil recruitment 📉 ↓ Serum C3 = marker of disease activity ⏱ Symptoms: Fever, urticaria, arthritis, lymphadenopathy, proteinuria (~10 days post exposure)

Question 51

What’s the key morphologic finding in HS3

Answer 51

🧱 Acute vasculitis with: 🔥 Neutrophilic infiltrate 🧬 Immune complex & complement deposits 💀 Fibrinoid necrosis (smudgy eosinophilic tissue damage) 🔬 Granular Ig + C3 on IF 🧲 Electron-dense deposits on EM (kidney)

Question 51

What happens in chronic serum sickness?

Answer 51

🕰 Repeated/prolonged antigen exposure → Persistent immune complexes 🧬 Example: Systemic Lupus Erythematosus (SLE) 🧠 Persistent Ab responses to autoantigens 🧪 Immune complex deposition continues

Question 51

What is the Arthus Reaction?

Answer 51

📍 Localized Type III Hypersensitivity 🧫 Intracutaneous Ag in a sensitized individual → local Ag-Ab complexes 🧨 Result: Vasculitis 💀 Fibrinoid necrosis ⛔ Thrombosis → worsens ischemia

Question 51

What is Type IV (T Cell–Mediated) Hypersensitivity?

Answer 51

👉 Caused mainly by cytokine-mediated inflammation from CD4+ T cells, and cytotoxicity by CD8+ T cells. 🧪 Triggered by environmental or self antigens. ⚠️ Major cause of autoimmune & chronic inflammatory diseases.

Question 52

What is Delayed-Type Hypersensitivity (DTH)?

Answer 52

🩺 Prototype of CD4+ T-cell–mediated inflammation. 📍 Occurs 24–48 hrs after antigen exposure in a previously sensitized person. 🔥 Involves Th1 (macrophage-rich) or Th17 (neutrophil-rich) responses.

Question 52

Role of CD8+ T Cells in Type IV Hypersensitivity?

Answer 52

💀 Direct cytotoxic killing of antigen-expressing cells. ⚔️ Especially involved in viral infections and some autoimmune reactions.

Question 52

What is the Tuberculin Reaction (DTH example)?

Answer 52

Intracutaneous PPD injection → local skin reaction in 8–12 hrs, peaks at 24–72 hrs. 🔬 Histology: Perivascular CD4+ T cells & macrophages Endothelial hypertrophy 📍 Clinical use: Test for prior TB exposure.

Question 53

What is granulomatous inflammation in chronic DTH?

Answer 53

🧬 Caused by persistent antigens (e.g., TB bacilli). 🧪 Th1 cytokines (mainly IFN-γ) activate macrophages → become epithelioid cells. 🌀 Form granulomas (epithelioid cells + lymphocytes). 💎 Seen in: TB, sarcoidosis, Crohn's, leprosy.

Question 54

What causes eosinophil-rich granulomas?

Answer 54

🪱 Helminthic infections (e.g., schistosomiasis) 📣 Driven by Th2 responses → eosinophil-dominant granulomas around parasitic eggs.

Question 55

What is Contact Dermatitis?

Answer 55

🔥 DTH to environmental agents (e.g., urushiol from poison ivy/oak). 👩‍🔬 Chemical modifies self-proteins → seen as foreign by T cells. 🧬 May also alter HLA molecules, triggering T cell attack. 📍 Results in itchy, vesicular rash.

Question 56

What causes Drug Reactions (T cell–mediated)?

Answer 56

🧪 Drugs modify self-proteins or HLA molecules → neoantigens 📍 Results in skin rashes, commonly T cell–mediated.

Question 57

What diseases involve CD4+ T cell–mediated inflammation?

Answer 57

🧠 Multiple sclerosis 🦵 Rheumatoid arthritis 💩 Inflammatory bowel disease (IBD) 🧬 Mechanism: Self-antigens drive persistent Th1/Th17 responses → chronic inflammation & tissue injury.

Question 57

What is CD8+ T Cell–Mediated Cytotoxicity?

Answer 57

🎯 CTLs recognize antigen on class I MHC of target cells → kill them directly. 🧪 Mechanisms: Perforin + Granzymes → caspase activation → apoptosis FasL–Fas binding → activates death receptors → apoptosis Also secrete IFN-γ, contributing to inflammation

Question 57

Clinical roles of CD8+ CTLs?

Answer 57

🦠 Viral infections: Kill infected cells → helps clear virus but can damage tissue (e.g., hepatitis) 🩸 Type 1 diabetes: Kill insulin-producing β cells 💉 Graft rejection: Kill cells expressing mismatched MHC 🧫 Tumor immunity: Kill cancer cells expressing tumor antigens

Question 57

What are the two main types of self-tolerance?

Answer 57

Central Tolerance 🏛️ Occurs in primary lymphoid organs (thymus & bone marrow) Deletes or alters immature self-reactive T and B cells Peripheral Tolerance 🌐 Occurs outside central lymphoid organs Controls self-reactive lymphocytes that escape into the periphery

Question 57

How is central tolerance established in T cells?

Answer 57

🔹 Occurs in thymus 🔹 Immature T cells that strongly recognize self-antigen → undergo apoptosis 🔹 This is called negative selection or clonal deletion 🔹 Some CD4+ T cells become regulatory T cells instead of being deleted

Question 57

What is the role of AIRE in central tolerance?

Answer 57

🧠 AIRE (Autoimmune Regulator): 🔹 Stimulates expression of peripheral tissue-restricted antigens in the thymus 🔹 Enables deletion of T cells that react to these antigens ❌ Mutation in AIRE → Autoimmune Polyendocrine Syndrome 🦠 (autoimmunity against multiple endocrine organs)

Question 58

How is central tolerance established in B cells?

Answer 58

🔹 Occurs in bone marrow 🔹 Strong recognition of self-antigen triggers: Receptor editing 🔁 Reactivates gene rearrangement machinery Creates new, non–self-reactive receptors Apoptosis 💀 If editing fails, the self-reactive B cell is deleted

Question 58

What are Regulatory T Cells (Tregs), and how do they suppress autoimmunity?

Answer 58

Express: FOXP3 (master transcription factor) 🧬 CD25 (IL-2Rα) ➕ CTLA-4 📌 Mechanisms of suppression: Produce IL-10 and TGF-β → ⬇️ T cell activation & macrophage response CTLA-4 competes with CD28 to block co-stimulation Consume IL-2 → deprives other T cells of growth signals 📍Clinical correlations: 🧬 FOXP3 mutation → IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) 👶 Seen in infants 🛑 Autoimmunity: type 1 diabetes, severe diarrhea, thyroiditis, eczema

Question 59

How do FOXP3 and CD25 deficiencies cause disease?

Answer 59

FOXP3 deficiency = ❌ Regulatory T cell development 📍 Leads to IPEX syndrome CD25 mutations → defective IL-2 signaling → impaired Treg survival/function → 📍 Linked to Type 1 diabetes and other autoimmune conditions

Question 59

What triggers mitochondrial apoptosis in self-reactive T cells in the periphery?

Answer 59

🧠 T cells recognizing self-antigen without full activation fail to induce anti-apoptotic proteins (Bcl-2, Bcl-x) ➡ This leaves Bim (a pro-apoptotic Bcl family protein) unopposed ⚡ Result: Apoptosis via the intrinsic (mitochondrial) pathway

Question 59

How does the Fas-FasL system eliminate self-reactive lymphocytes?

Answer 59

T cells recognizing self antigens co-express: Fas (CD95) = death receptor Fas Ligand (FasL) = expressed by activated T cells 💥 Fas-FasL interaction activates the extrinsic (death receptor) apoptosis pathway it can also delete self reactive B cells via death receptor pathway

Question 60

A: Autoimmune Lymphoproliferative Syndrome (ALPS)

Answer 60

🔁 Mutations in Fas or FasL prevent deletion of self-reactive lymphocytes ⚠️ Resembles SLE 🩸 Features: Lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias

Question 60

What are immune-privileged sites and why are they significant in tolerance?

Answer 60

Sites like eye, testis, brain don’t communicate well with blood/lymph 🧬 Antigens in these sites are hidden → no immune recognition ➡ tolerance

Question 60

Clinical consequence of antigen release from immune-privileged sites?

Answer 60

🧬 Trauma or infection may release hidden self-antigens ⚠️ Leads to immune attack and tissue damage Examples: Post-traumatic orchitis 🥚 Autoimmune uveitis 👁️

Question 60

What maintains the balance between immune defense and self-tolerance?

Answer 60

🧠 A delicate equilibrium between: ✅ Lymphocyte activation (defense vs. pathogens) ⛔ Mechanisms of tolerance (prevents autoimmunity) 🛑 Autoimmune disease = failure of tolerance → immune attack on self-antigens

Question 61

What triggers autoimmunity?

Answer 61

Autoimmunity = 🔁 Genetic susceptibility + Environmental triggers 🧬 Susceptibility genes = disrupt tolerance 🦠 Infections/tissue damage = activate self-reactive lymphocytes ➡ Initiates autoimmune response

Question 61

What mechanisms may lead to breakdown of tolerance?

Answer 61

➡️ Defective tolerance/regulation: Observed in rare Mendelian autoimmune syndromes or knockout mice Unknown in most common autoimmune diseases ➡️ Abnormal display of self antigens: ↑ Expression/persistence of self antigens Modified or "neoantigen" formation due to stress/injury ➡️ Inflammation/innate immune activation: Microbes or tissue injury trigger local inflammation This can act as a spark for autoimmunity

Question 61

Which genetic elements are most strongly associated with autoimmune diseases?

Answer 61

➡️ HLA genes (especially class I & II) E.g., HLA-B27 → ↑ risk of ankylosing spondylitis (100-200x!) 🦴🔥 Other autoimmune diseases linked to class II alleles 📌 Note: Having a risky allele ≠ disease guarantee — most carriers stay healthy

Question 61

Autoimmune diseases arise from failure of self-tolerance due to:

Answer 61

Genetic susceptibility (esp. HLA alleles, but not sufficient alone) Environmental triggers (infection, tissue injury) that activate self-reactive lymphocytes Defective tolerance mechanisms: Anergy, deletion, lack of regulation Abnormal self-antigen presentation: Neoantigens, persistent antigens Innate immune activation/inflammation as a trigger 🔬 Many hypotheses exist, but exact mechanisms in most human diseases remain unclear.

Question 61

What is the role of PTPN22 polymorphisms in autoimmunity?

Answer 61

PTPN22 encodes a protein tyrosine phosphatase that normally dampens lymphocyte activation. Disease-associated variants are functionally defective, leading to excessive T/B cell activation. Associated with: 🔹 Rheumatoid arthritis (RA) 🔹 Type 1 diabetes (T1D) 🔹 Inflammatory bowel disease (IBD)

Question 61

How do NOD2 and IL2RA polymorphisms contribute to autoimmunity?

Answer 61

NOD2 (in Crohn disease): A microbial sensor in intestinal epithelial cells (Paneth cells). Mutated variant leads to impaired sensing of gut commensals, triggering chronic inflammation. IL2RA (CD25): Encodes IL-2 receptor α chain, key for regulatory & effector T cell balance. Polymorphisms may reduce regulatory T cell function, contributing to MS, T1D.

Question 61

What single-gene mutations are known to cause autoimmunity despite being rare?

Answer 61

CTLA4: Interferes with T cell inhibition → T1D, RA AIRE: Defective thymic self-antigen presentation → APS-1 PD-1: Loss leads to unchecked T cell activation FAS/FASL: Loss prevents T-cell apoptosis → ALPS IL-2/CD25: Defective Treg maintenance → IPEX

Question 62

What are two major ways infections trigger autoimmunity? A:

Answer 62

Costimulation upregulation ➡️ Infection induces APCs to express costimulators; if self-antigens are presented, self-reactive T cells are activated. Molecular mimicry ➡️ Microbial antigens resemble self-antigens, activating autoreactive lymphocytes. Classic example: 🦠 Streptococcus → antibodies cross-react with myocardium → 🫀 rheumatic heart disease

Question 63

What are other ways infections may contribute to autoimmunity? A:

Answer 63

Polyclonal B-cell activation (e.g., by EBV, HIV) → autoantibody production Tissue injury → release/alteration of self-antigens (neoantigens) Proinflammatory cytokines → recruit self-reactive lymphocytes But: Some infections protect against autoimmunity (e.g., ↓ T1D in infected mice) via IL-2 and Treg support.

Question 63

Why are autoimmune diseases typically chronic and progressive?

Answer 63

Amplification loops in immune system maintain response Epitope spreading: immune attack on one self-antigen → more tissue damage → exposure of new epitopes → new lymphocytes activated

Question 63

Systemic Lupus Erythematosus (SLE) — Overview

Answer 63

🔹 Definition: Chronic autoimmune disease with injury caused mainly by immune complex deposition (Type III hypersensitivity) and some Type II reactions. 🔹 Key Feature: 🧪 Antinuclear antibodies (ANAs) against DNA, histones, ribonucleoproteins, etc. 🔹 Organs Affected: 🩸 Skin, joints, kidneys, serosa—can involve almost any organ. 🔹 Course: Chronic, remitting/relapsing, febrile.

Question 63

Lupus diagnosis Hallmark?

Answer 63

nti-dsDNA & Anti-Sm (Smith antigen) = 🎯 highly specific 🔸 ANA Categories: 1️⃣ DNA 2️⃣ Histones 3️⃣ Non-histone proteins bound to RNA 4️⃣ Nucleolar antigens 🔸 Detection: 🧬 Indirect immunofluorescence (IF) 🟢 Homogeneous: chromatin, histones, dsDNA 🟠 Rim/peripheral: dsDNA 🟣 Speckled: Sm, ribonucleoprotein, SS-A/B ⚪ Nucleolar: RNA, systemic sclerosis 🟡 Centromeric: centromere-specific, systemic sclerosis

Question 63

Antiphospholipid antibodies in lupus

Answer 63

Target phospholipid-protein complexes (e.g., β2-glycoprotein I) Bind cardiolipin → 🧪 False + syphilis test Interfere with aPTT in vitro → "Lupus anticoagulant" In vivo = Hypercoagulable → thrombosis, miscarriage risk

Question 63

The following 6 immunologic markers are used to help diagnose SLE:

Answer 63

🔹 1. Antinuclear Antibody (ANA) — Abnormal titer by immunofluorescence — Highly sensitive, but not specific 🧬 2. Anti–Double-Stranded DNA (anti-dsDNA) — Abnormal titer — Specific for SLE — Levels correlate with disease activity, especially lupus nephritis 🧬 3. Anti-Smith (anti-Sm) Antibody — Presence of anti-Sm nuclear antigen — Highly specific, but low sensitivity 🧫 4. Antiphospholipid Antibodies (aPL) Satisfy any one of the following:  1️⃣ Elevated IgG or IgM anti-cardiolipin  2️⃣ Positive lupus anticoagulant test  3️⃣ False-positive syphilis serology (for ≥6 months), confirmed by ❌ negative FTA-ABS or TPHA 🧊 5. Low Complement Levels — ↓ C3, C4, or CH50 — Indicates complement consumption from immune complex deposition 🩸 6. Positive Direct Coombs Test — Detects anti–RBC antibodies — Must be positive in absence of hemolytic anemia

Question 63

What is the fundamental defect in the pathogenesis of SLE?

Answer 63

Loss of self-tolerance The immune system fails to recognize self-antigens as harmless Leads to activation of autoreactive lymphocytes and autoantibody production

Question 64

What genetic factors contribute to SLE?

Answer 64

Genetic Predisposition 👨‍👩‍👧 Family history increases risk; 20% of first-degree relatives may have autoantibodies 👯‍♂️ Higher concordance in monozygotic twins (>20%) than dizygotic (1–3%) 🧬 MHC genes (HLA-DQ alleles) linked to anti-dsDNA, anti-Sm, antiphospholipid Abs ❌ Complement deficiencies (C1q, C2, C4) → impaired immune complex clearance & self-tolerance loss 🧪 GWAS: Many risk loci involved in lymphocyte signaling & type I IFN responses ➡️ Genetic factors account for <20% of risk → environment also important

Question 64

What are the key immunologic abnormalities in SLE?

Answer 64

🛑 Immune Dysregulation ❌ Failure to delete autoreactive B cells (central & peripheral tolerance defects) 🧫 CD4+ T cells help B cells target nucleosomal (nuclear) antigens 🔁 TLRs (e.g., TLR7, TLR9) activated by self-DNA/RNA in immune complexes → stimulate B cells 🧬 Type I IFNs (e.g., IFN-α) → promote DC/B cell activation & Th1 skewing 📈 IFN signature in blood correlates with disease severity

Question 65

What environmental factors contribute to SLE pathogenesis?

Answer 65

🌍 Environmental Triggers ☀️ UV light: Induces apoptosis, modifies DNA to enhance TLR recognition, increases IL-1 🚺 Sex hormones: Estrogen linked to higher risk; genes on X chromosome also implicated 💊 Drug-induced lupus: e.g., hydralazine, procainamide, D-penicillamine

Question 66

What is the main mechanism behind systemic lesions in SLE?

Answer 66

Type III Hypersensitivity (Immune Complex-Mediated) 🔁 Circulating DNA–anti-DNA immune complexes deposit in tissues 🧠 Especially in glomeruli and small vessels ⬇️ Low serum complement (due to consumption) 🔬 Granular deposits of Ig and complement in glomeruli 🔥 T-cell infiltrates may also contribute to tissue damage

Question 66

What are LE bodies and LE cells?

Answer 66

🔵 LE Bodies (Hematoxylin Bodies): Form when ANAs bind to exposed nuclear material in damaged cells ➡️ Nuclei lose chromatin pattern, appear homogeneous 🧫 LE Cells: Phagocytes (neutrophils or macrophages) that have engulfed these altered nuclei Used historically in diagnosing SLE via in vitro testing

Question 66

How does SLE cause cytopenias?

Answer 66

🛑 Type II Hypersensitivity (Antibody-Mediated) 🔬 Autoantibodies against RBCs, WBCs, and platelets 📉 Promote opsonization → phagocytosis → cytopenias ⚠️ Especially causes immune thrombocytopenic purpura (ITP) 🧬 Autoantibodies bind platelet membrane glycoproteins 📍 Platelets cleared by splenic macrophages

Question 66

What is antiphospholipid antibody syndrome (APS) in SLE?

Answer 66

⚠️ Secondary APS (in context of lupus): 🩸 Causes venous & arterial thromboses 🚼 Leads to recurrent miscarriages, strokes, or vision loss 🧪 Autoantibodies may target: Clotting factors Platelets Endothelial cells 🧍‍♀️ If APS occurs without SLE, it's called Primary APS

Question 66

What causes neuropsychiatric symptoms in SLE?

Answer 66

CNS involvement in SLE: Autoantibodies cross blood-brain barrier Target neurons or neurotransmitter receptors 💬 May contribute to cognitive dysfunction, mood changes 🔥 Cytokines may also play a role in CNS symptoms

Question 67

What organs are most characteristically affected in SLE and by what mechanism?

Answer 67

🧬 Immune Complex Deposition (🧪 Type III Hypersensitivity) 📍 Affects: 🩸 Blood vessels 🧠 Kidneys 🧍 Connective tissue 🧑‍🦰 Skin

Question 67

What are the vascular changes seen in SLE?

Answer 67

🧨 Acute Necrotizing Vasculitis Involves capillaries, small arteries & arterioles 🧪 Fibrinoid necrosis of vessel walls 🧱 Chronic stages: fibrous thickening → luminal narrowing

Question 67

What renal pathology is seen in SLE and how is it classified?

Answer 67

🧫 Seen in up to 50% of SLE patients 🧬 Caused by immune complex deposition in: Glomerular basement membrane Mesangium Tubular & peritubular capillary basement membranes 📚 6 Classes of Lupus Nephritis (Class I–VI)

Question 67

What are the 6 classes of lupus nephritis?

Answer 67

Class I: Minimal Mesangial Immune deposits in mesangium (seen on EM/IF only) Class II: Mesangial Proliferative Mesangial hypercellularity, matrix ↑, Ig + C deposits Class III: Focal Lupus Nephritis <50% glomeruli; segmental/global; hematuria ± RBC casts Class IV: Diffuse Lupus Nephritis ≥50% glomeruli; "wire loops", crescents, subendothelial deposits Subtypes: IV-S (segmental), IV-G (global) Class V: Membranous Subepithelial immune deposits; severe proteinuria/nephrotic Class VI: Advanced Sclerosing 90% glomeruli sclerosed → ESRD

Question 67

What are the cutaneous findings in SLE?

Answer 67

Malar (“butterfly”) rash: ~50% of cases Similar lesions on trunk/extremities Triggered or worsened by sunlight 🧪 Other: urticaria, bullae, maculopapular rashes, ulcers 🔬 Histology: vacuolar degeneration of basal layer, dermal edema, perivascular inflammation 🧬 Ig & complement deposits at dermoepidermal junction

Question 68

What are the joint and CNS findings in SLE?

Answer 68

🦴 Joints: Nonerosive synovitis No deformity (unlike RA) 🧠 CNS: Neuropsychiatric symptoms (no clear morphologic cause) Sometimes noninflammatory vessel occlusion (due to endothelial injury)

Question 69

How does SLE affect the serosa and heart?

Answer 69

🫀 Serosal membranes: Acute: fibrinous exudate Chronic: fibrous thickening → adhesions/obliteration 💧Pleural & pericardial effusions common 💗 Heart involvement: Pericarditis (up to 50%) Myocarditis (rare; tachycardia, ECG changes) Libman-Sacks endocarditis: Nonbacterial, verrucous 1–3 mm vegetations on either side of valves 💔 May also cause mitral/aortic valve dysfunction (thickening, stenosis, regurgitation)

Question 69

What vascular complications can SLE patients develop?

Answer 69

🫀 Coronary artery disease (CAD) Occurs even in young SLE patients Linked to: Corticosteroid use Traditional risk factors (HTN, obesity, hyperlipidemia) Immune complex–mediated endothelial damage Antiphospholipid antibodies

Question 70

What are the splenic and pulmonary findings in SLE?

Answer 70

🧫 Spleen: Splenomegaly Capsular thickening Onion-skin lesions: concentric smooth muscle & intimal hyperplasia 🫁 Lungs: Pleuritis & pleural effusions (~50%) Chronic interstitial fibrosis May lead to secondary pulmonary hypertension

Question 71

What are the findings in bone marrow, lymph nodes, and other tissues in SLE?

Answer 71

🩸 LE (hematoxylin) bodies: Found in bone marrow & other tissues Strongly indicative of SLE 🧠 Lymph nodes: Hyperplastic germinal centers May show necrotizing lymphadenitis ⚠️ Dense CTL/macrophage infiltrates can mimic T-cell lymphoma, but are polyclonal/reactive

Question 72

Kidneys – Lupus Nephritis (seen in ~50%) just read

Answer 72

Due to immune complex deposition (GBM, mesangium, tubular/peritubular basement membranes) 🧪 6 Histologic Classes (some overlap/evolution over time): Class I – Minimal Mesangial: Deposits seen only by EM/IF No LM changes Class II – Mesangial Proliferative: Mesangial cell/matrix proliferation Granular Ig/complement deposits Class III – Focal (<50% glomeruli): Segmental or global lesions Endothelial/mesangial proliferation, necrosis, crescents RBC casts, hematuria, proteinuria Class IV – Diffuse (≥50% glomeruli): Most common & severe Segmental (IV-S) or global (IV-G) Crescents, wire loops (subendothelial deposits), hematuria, proteinuria, hypertension, renal insufficiency Class V – Membranous: Subepithelial deposits Thickened capillary walls Nephrotic syndrome Class VI – Advanced Sclerosing: 90% glomeruli sclerosed End-stage renal disease Tubulointerstitial Lesions: Often present; rarely dominant Immune deposits in tubular/peritubular membranes B-cell follicles in interstitium may produce autoantibodies

Question 72

Skin involvment in LUPUS just read

Answer 72

Malar ("butterfly") rash (~50%) Also on trunk/extremities Triggered/worsened by sunlight Other lesions: urticaria, bullae, maculopapular, ulcers Histology: vacuolar basal degeneration, dermal edema, perivascular inflammation Immunofluorescence: Ig & complement deposits at dermoepidermal junction (also in uninvolved skin)

Question 72

Serosal Cavities (Pleura, Pericardium, Peritoneum) in LUPUS

Answer 72

Pleuritis/pericarditis (effusions common) Acute: fibrinous exudate Chronic: thickened, shaggy fibrous adhesions → obliteration

Question 73

Heart in lupus

Answer 73

Pericarditis (symptomatic/asymptomatic) in ~50% Myocarditis (rare): tachycardia, ECG changes Valvular disease: mitral/aortic thickening → stenosis/regurgitation Libman-Sacks Endocarditis: Nonbacterial, verrucous 1–3 mm vegetations on either leaflet surface (unlike rheumatic or infective endocarditis)

Question 74

What are the typical clinical features of systemic lupus erythematosus (SLE)?

Answer 74

Usually a young woman with: 🦋 Malar (butterfly) rash 🌡️ Fever 🦴 Non-deforming joint pain (peripheral joints) 💨 Pleuritic chest pain ☀️ Photosensitivity 📉 May also present subtly: Fever of unknown origin Abnormal urinalysis Mimics of RA or rheumatic fever Psychosis, seizures Coronary artery disease Cytopenias (anemia, thrombocytopenia)

Question 75

What laboratory findings support a diagnosis of SLE?

Answer 75

Serologic & morphologic findings: ANA: ✳️ Present in almost 100% (not specific) Anti-dsDNA, anti-Sm (more specific) Hematuria, RBC casts, proteinuria Nephrotic syndrome possible Cytopenias: anemia, leukopenia, thrombocytopenia 🔻 Complement levels during flares (hypocomplementemia)

Question 76

What is the typical disease course and prognosis of SLE?

Answer 76

Variable & unpredictable course: Rarely fulminant with early death More often: relapsing-remitting over years/decades 🧪 Flares: immune complex formation → ↓ complement 💊 Managed with corticosteroids & immunosuppressives ✅ 5-year survival: ~90% ✅ 10-year survival: ~80% ⚠️ Major causes of death: renal failure, infections, coronary artery disease

Question 76

What is Sjögren Syndrome, and how does it typically present?

Answer 76

🧬 Sjögren Syndrome is a chronic autoimmune disease characterized by: 👁️ Dry eyes (keratoconjunctivitis sicca) 👄 Dry mouth (xerostomia) Caused by immune-mediated destruction of lacrimal and salivary glands. 🔹 Two forms:  * Primary (sicca syndrome) – isolated  * Secondary – associated with other autoimmune diseases, especially rheumatoid arthritis

Question 77

What are the key immunologic features of Sjögren Syndrome?

Answer 77

🔬 Immune markers include: 🔸 Rheumatoid factor (RF) in ~75% (even w/o RA) 🔸 ANA positivity in 50–80% ⭐ Anti-SS-A (Ro) and Anti-SS-B (La) antibodies in up to 90% — important serologic markers 🧪 Other organ-specific and non-specific autoantibodies may also be present

Question 77

What is chronic discoid lupus erythematosus (CDLE)?

Answer 77

Skin-limited lupus variant: Edematous, erythematous, scaly plaques with follicular plugging & atrophy 📏 Well-defined raised erythematous borders Systemic disease rare, but 5–10% may develop SLE 🔬 35% ANA-positive; anti-dsDNA rarely present 💡 Immunofluorescence: Ig & C3 at dermoepidermal junction

Question 77

What distinguishes subacute cutaneous lupus erythematosus (SCLE) from CDLE and SLE?

Answer 77

🌞 SCLE = intermediate form with: Widespread, superficial, nonscarring rash Mild systemic SLE-like symptoms 🧬 Strong association: Anti-SS-A (Ro) antibodies HLA-DR3 genotype

Question 77

What is the pathogenesis of Sjögren Syndrome?

Answer 77

Still incompletely understood, but involves: 🔹 CD4+ T cells and B cell activation → infiltrate and destroy glands ⚔️ Trigger may be a viral infection of salivary glands → self-antigen release 🧬 Genetic susceptibility (weak HLA associations) 🔁 Aberrant immune responses → chronic inflammation → fibrosis

Question 77

What is the morphology of affected glands in Sjögren Syndrome?

Answer 77

Histologic features: 🧫 Intense lymphocytic infiltrates (mainly CD4+ T cells, B cells, and plasma cells) 🧱 Progressive fibrosis of lacrimal/salivary glands 🧬 Chronic stimulation may lead to monoclonal B-cell expansion → risk of marginal zone lymphoma (5% risk, 40x normal)

Question 77

What complications can occur in Sjögren Syndrome?

Answer 77

⚠️ Major complications: 🧪 Tubulointerstitial nephritis → renal tubular defects (acidosis, uricosuria, phosphaturia) 🧬 High risk of marginal zone B-cell lymphoma (esp. in glands) 🤝 Often coexists with other autoimmune diseases like RA, SLE, polymyositis, scleroderma, thyroiditis

Question 78

What drugs can induce a lupus-like syndrome (DILE)?

Answer 78

💊 Hydralazine, procainamide, isoniazid, D-penicillamine Also: anti-TNF agents (surprisingly) 📈 ANA often positive (e.g. 80% with procainamide) ❗ Only ~⅓ develop symptoms: arthralgia, fever, serositis 🚫 Renal & CNS involvement are rare 🧬 High frequency of anti-histone antibodies (vs. anti-dsDNA in SLE)

Question 79

What is Mikulicz Syndrome, and how is it related to Sjögren?

Answer 79

Mikulicz syndrome = enlargement of lacrimal + salivary glands 🔍 Can be caused by: 🔸 Sjögren syndrome 🔸 Sarcoidosis 🔸 IgG4-related disease 🔸 Lymphoma or other tumors 🛑 Mikulicz “disease” is outdated — now classified under Mikulicz syndrome

Question 79

What are the three key pathologic features of systemic sclerosis (scleroderma)?

Answer 79

Chronic inflammation due to presumed autoimmunity Widespread small vessel damage Progressive fibrosis in skin & internal organs

Question 80

Which organs are commonly affected in systemic sclerosis?

Answer 80

Skin (most common) GI tract Kidneys Heart Lungs Skeletal muscles

Question 80

What are the two major clinical forms of systemic sclerosis?

Answer 80

1- Diffuse scleroderma: Widespread skin involvement at onset Rapid progression Early visceral involvement 2- Limited scleroderma: Skin involvement limited to fingers, forearms, face Visceral involvement occurs late More benign course

Question 80

What is CREST syndrome, and which form is it associated with?

Answer 80

CREST is a subset of limited scleroderma: Calcinosis Raynaud phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia

Question 80

What are the 3 interrelated processes involved in systemic sclerosis pathogenesis?

Answer 80

Autoimmunity Vascular damage Collagen deposition & fibrosis

Question 80

What is the proposed role of CD4+ T cells in systemic sclerosis?

Answer 80

Respond to unknown antigens Accumulate in skin and secrete cytokines that: Activate inflammatory cells Stimulate fibroblasts

Question 80

Which cytokines contribute to fibrosis in systemic sclerosis?

Answer 80

TGF-β IL-13 ⬆️ These stimulate fibroblast production of: Collagen Fibronectin Other ECM proteins

Question 81

Which immune cells and antibodies are involved in systemic sclerosis autoimmunity?

Answer 81

Activated CD4+ T cells (especially Th2 subtype) Autoantibodies, especially: ANA (antinuclear antibodies)

Question 81

What is the nature of vascular damage in systemic sclerosis?

Answer 81

💥 Microvascular injury is an early and consistent finding 🧠 May be initial trigger in disease 🧬 Key features: 🧪 Intimal proliferation in digital arteries 🧪 Capillary dilation, destruction, and leakage 🧪 Distorted or absent nailfold capillary loops 🧪 ↑ von Willebrand factor (endothelial activation) 🧪 ↑ circulating platelet aggregates

Question 81

What mediators are involved in vascular-related fibrosis?

Answer 81

🧬 Repeated endothelial injury → platelet aggregation 🧪 Release of profibrotic factors:  🧬 PDGF  🧬 TGF-β 🔁 Triggers perivascular fibrosis 🧠 Vascular smooth muscle also shows ↑ adrenergic receptors → contributes to vascular tone abnormalities

Question 81

How does fibrosis progress in systemic sclerosis?

Answer 81

📌 Driven by: 🧠 Alternatively activated macrophages 🧠 Fibrogenic cytokines from leukocytes 🧠 Hyperresponsive fibroblasts to cytokines 🧠 Ischemia from vascular injury → secondary scarring

Question 81

What are the characteristic skin changes in systemic sclerosis?

Answer 81

🔹 Begins in fingers/distal upper limbs → spreads proximally (face, neck, arms) 🔹 Histology: CD4+ T cells, edema, degenerated eosinophilic collagen 🔹 Dermal fibrosis with tightly bound skin 🔹 Compact dermal collagen, thin epidermis, lost rete pegs 🔹 Dermal appendage atrophy, hyaline thickening of vessels 🔹 Subcutaneous calcifications (esp. in CREST) 🔹 Clawlike fingers, mask-like face 🔹 Ulcerations, terminal phalanx atrophy, autoamputation

Question 81

How does systemic sclerosis affect the alimentary (GI) tract?

Answer 81

Seen in ~90% of patients 🔹 Muscularis atrophy & collagenous fibrosis (esp. esophagus) 🔹 Lower 2/3 of esophagus becomes rigid (“rubber hose”) 🔹 Lower sphincter dysfunction → GERD, strictures, Barrett esophagus 🔹 Mucosal thinning & ulceration 🔹 Collagen in lamina propria/submucosa 🔹 Small bowel: villous atrophy → malabsorption

Question 82

What are the musculoskeletal manifestations of systemic sclerosis? 🩺 A4:

Answer 82

🔹 Early: Synovial inflammation, hypertrophy, hyperplasia 🔹 Late: Synovial fibrosis 🔹 Mimics rheumatoid arthritis but 🛑 minimal joint destruction 🔹 ~10% may develop inflammatory myositis

Question 82

How are the kidneys affected in systemic sclerosis?

Answer 82

🧪 In 2/3 of patients 🔹 Interlobular arteries: intimal thickening from mucin/collagen 🔹 Resemble malignant HTN but limited to 150–500 μm vessels 🔹 Hypertension in 30%, malignant HTN in 20% (⬆️ risk of death) 🔹 Malignant HTN: fibrinoid necrosis, thrombosis, infarction 🔹 🔴 Renal failure = cause of death in ~50% of cases

Question 82

What are the pulmonary complications of systemic sclerosis?

Answer 82

🔹 Seen in >50% of patients 🔹 Interstitial fibrosis (like idiopathic pulmonary fibrosis) 🔹 Pulmonary hypertension due to endothelial dysfunction 🔹 Pulmonary vasospasm contributes to hypertension

Question 83

What cardiac lesions are seen in systemic sclerosis?

Answer 83

🔹 Pericarditis with effusion 🔹 Myocardial fibrosis 🔹 Thickening of intramyocardial arterioles 🧪 Myocardial dysfunction is histologically common but less often symptomatic

Question 84

What are the key clinical features and demographics of systemic sclerosis?

Answer 84

✨ Distinctive feature = Striking skin fibrosis ❄️ Raynaud phenomenon: Seen in virtually all patients; precedes other symptoms in 70% 🍽️ Dysphagia from esophageal fibrosis + hypomotility (>50% of patients) 🍔 Malabsorption (due to small bowel involvement): Leads to weight loss + anemia 😮‍💨 Pulmonary fibrosis → Respiratory issues + right heart dysfunction ❤️ Myocardial fibrosis → Arrhythmias or heart failure 🧪 Proteinuria in ~30%, nephrotic syndrome is rare ⚠️ Malignant hypertension is most serious → may lead to renal failure 🧑🏿‍🦱 More severe in people of African descent, esp. women ⚰️ Leading cause of death now = pulmonary disease (used to be renal crises)

Question 84

Which autoantibodies are key in systemic sclerosis, and what are their clinical associations?

Answer 84

🧬 Virtually all patients: +ANA (various patterns) 🧪 Anti–topoisomerase I (anti-Scl 70): 🎯 Highly specific 🫁 Associated with diffuse disease, pulmonary fibrosis, peripheral vascular disease 🧪 Anti-centromere antibodies: 🧤 Seen in limited cutaneous disease (CREST) 🕊️ Associated with longer survival, delayed/absent visceral involvement ❗ May still get esophageal lesions, pulmonary HTN, biliary cirrhosis

Question 84

What is mixed connective tissue disease and how does it present?

Answer 84

🧪 Serology: High titers of anti–U1 RNP 🧍‍♀️ Overlaps with SLE, systemic sclerosis, and polymyositis 📋 Clinical features: 🤏 Finger synovitis ❄️ Raynaud phenomenon 💪 Myositis 🧫 Mild renal involvement (responds well to steroids) 🌀 May evolve into SLE or systemic sclerosis, or remain mixed 💊 Steroid-responsive, but not always → suggests distinct disease

Question 84

What is IgG4-related disease and what are its key features?

Answer 84

🧪 Tissue infiltrates: IgG4+ plasma cells, lymphocytes (esp. T cells) 🧱 Dense fibrosis + obliterative phlebitis 🧬 ↑ Serum IgG4 👴 Affects mostly middle-aged to older men 🧠 Can affect virtually any organ, including: Pancreas, bile ducts, kidneys, salivary glands, lungs, thyroid, meninges, etc. 🧊 Many previously isolated diseases now recognized as IgG4-RD (e.g. Mikulicz, Riedel thyroiditis) ❓ Pathogenesis unclear: No known autoantigen, but B cells likely involved 💊 Responds to rituximab → B-cell role supported

Question 85

What are allografts and xenografts?

Answer 85

🔹 Allografts: Grafts between individuals of the same species 🔹 Xenografts: Grafts between different species (experimental)

Question 85

What triggers transplant rejection?

Answer 85

🔹 Activation of T lymphocytes and antibodies against donor graft antigens 🔹 Results in destruction of graft tissue

Question 85

What is the main source of antigenic difference that causes rejection?

Answer 85

🔹 HLA allele differences (MHC molecules) 🔹 HLA genes are highly polymorphic, so mismatch is almost inevitable (except in identical twins)

Question 86

What are the 2 pathways of T cell recognition of graft antigens?

Answer 86

Direct Pathway: 🔸 Donor APCs in the graft present donor HLA directly to recipient T cells 🔸 Important in acute rejection (CD8+ CTLs) Indirect Pathway: 🔸 Recipient APCs process and present graft antigens 🔸 More important in chronic rejection (CD4+ Th1 cytokine response)

Question 87

How do B cells participate in graft rejection?

Answer 87

🔹 Recognize donor antigens (e.g., HLA) 🔹 Require T cell help for activation 🔹 Produce alloantibodies that can mediate rejection

Question 87

What causes hyperacute rejection?

Answer 87

🔹 Preformed antibodies in the recipient react with graft endothelial antigens Blood group antigens (IgM) Allogeneic MHC (from prior exposure: transfusion, pregnancy, previous transplan

Question 87

When does hyperacute rejection occur?

Answer 87

🔹 Immediately after transplantation (minutes to hours) 🔹 Upon restoration of blood flow to the graft

Question 88

What is the pathogenesis of hyperacute rejection?

Answer 88

🔹 Preformed Abs bind graft endothelium → Complement activation 🔹 Leads to: 🔸 Endothelial injury 🔸 Thrombosis 🔸 Ischemic necrosis of the graft

Question 88

What is the gross appearance of a kidney undergoing hyperacute rejection?

Answer 88

🔹 Cyanotic, mottled, and anuric 🔹 Must be removed immediately

Question 88

🔬 What is the histology of hyperacute rejection in kidney?

Answer 88

🔹 Fibrinoid necrosis of arteriolar/arterial walls 🔹 Thrombotic occlusion of lumens 🔹 Neutrophilic infiltration in: Arterioles Glomeruli Peritubular capillaries 🔹 Thrombi in glomerular capillaries → cortical infarction

Question 88

⏱️ When does acute rejection occur, and what causes it?

Answer 88

🔹 Occurs within days to weeks after transplant 🔹 Mediated by T cells and antibodies against graft alloantigens 🔹 May also occur suddenly later if immunosuppression is reduced

Question 89

What are the two types of acute rejection?

Answer 89

Cellular (T cell–mediated) rejection Humoral (antibody-mediated) rejection 🔸 Both patterns often coexist

Question 89

What are the morphologic patterns of acute cellular rejection in the kidney?

Answer 89

Type I: Tubulointerstitial pattern 🔸 Interstitial inflammation and tubulitis 🔸 Infiltrates of activated CD4+ and CD8+ T cells Type II: Vascular rejection 🔸 Endothelial inflammation (endotheliitis / intimal arteritis) 🔸 Swollen endothelium, lymphocytes between endothelium and vessel wall Type III: Necrotizing vasculitis (severe vascular injury)

Question 89

💥 What is acute antibody-mediated rejection?

Answer 89

🔹 Antibodies bind vascular endothelium → classical complement activation 🔹 Leads to: 🔸 Endothelial damage 🔸 Inflammation of glomeruli & peritubular capillaries 🔸 Complement deposition (e.g., C4d) 🔸 Focal thrombosis in small vessels

Question 89

What is chronic rejection and when does it occur?

Answer 89

🔹 Slow, progressive graft failure over months or years 🔹 Main cause of long-term graft loss

Question 89

🧪 What are the key morphologic features of chronic rejection in kidney?

Answer 89

🔹 Vascular intimal thickening and occlusion (graft arteriosclerosis) 🔹 Glomerulopathy: Basement membrane duplication 🔹 Peritubular capillaritis with basement membrane multilayering 🔹 Interstitial fibrosis and tubular atrophy → parenchymal loss 🔹 Sparse mononuclear infiltrates

Question 89

What causes chronic rejection?

Answer 89

🔹 T cells secrete cytokines → activate fibroblasts & smooth muscle 🔹 Alloantibodies contribute 🔹 Largely resistant to therapy

Question 89

What is the role of HLA matching in graft survival?

Answer 89

🔹 Kidney: Matching HLA-A, B, and DR alleles is beneficial 🔹 Other organs: HLA matching less important (urgency, anatomy take priority)

Question 89

What are the key immunosuppressive drugs used?

Answer 89

🔹 Steroids: Reduce inflammation 🔹 Mycophenolate mofetil: Inhibits lymphocyte proliferation 🔹 Tacrolimus (FK506): 🔸 Inhibits calcineurin → blocks NFAT → ↓ IL-2 → ↓ T cell activation 🔹 Cyclosporine: Older calcineurin inhibitor

Question 89

What are advanced therapies for rejection?

Answer 89

🔹 T and B cell–depleting antibodies 🔹 IVIG: Suppresses inflammation (mechanism unclear) 🔹 Plasmapheresis: Removes antibodies in severe antibody-mediated rejection 🔹 Costimulation blockade: Prevents DC B7–CD28 interaction with host T cells

Question 89

What are complications of immunosuppression?

Answer 89

🔹 ↑ Risk of opportunistic infections and viral reactivation 🔹 Polyoma virus: Reactivates in kidney → tubulitis → graft loss 🔹 ↑ Risk of virus-associated cancers: 🔸 EBV → lymphomas 🔸 HPV → squamous cell carcinoma 🔸 HHV-8 → Kaposi sarcoma

Question 90

🧫 What conditions are treated with HSC transplants?

Answer 90

🔹 Hematologic malignancies (e.g., leukemia) 🔹 Bone marrow failure syndromes (e.g., aplastic anemia) 🔹 Inherited bone marrow disorders (e.g., sickle cell anemia, thalassemia) 🔹 Immunodeficiency states (e.g., SCID)

Question 90

What is graft-versus-host disease (GVHD), and why is it a concern?

Answer 90

🔹 Occurs when immunologically competent donor cells attack the immunocompromised recipient's tissues 🔹 Common in HSC transplantation but rare in solid organ transplants 🔹 HLA mismatch increases risk, so HLA matching is crucial

Question 90

What are the key features of acute GVHD?

Answer 90

🔹 Timing: Occurs within days to weeks after transplantation 🔹 Target organs: Skin: Rash, possible desquamation Liver: Destruction of small bile ducts → jaundice Gut: Mucosal ulceration → bloody diarrhea 🔹 T cells: Direct cytotoxicity (CD8+) and cytokine release by activated T cells

Question 90

What are the features of chronic GVHD?

Answer 90

🔹 Timing: Can follow acute GVHD or develop insidiously 🔹 Skin: Extensive damage, fibrosis (resembles systemic sclerosis) 🔹 Liver: Cholestatic jaundice 🔹 Gastrointestinal tract: Esophageal strictures 🔹 Immune system: Thymus involution Lymphocyte depletion Increased risk of autoimmunity Increased susceptibility to infections (e.g., CMV)

Question 90

🧑‍⚕️ What strategies help minimize GVHD?

Answer 90

🔹 T-cell depletion: Removing donor T cells reduces GVHD risk but may increase graft failures and EBV-related lymphoma 🔹 Graft-versus-leukemia effect: Donor T cells help fight leukemia cells, so complete depletion can hinder treatment of leukemic relapse

Question 90

What are the risks of immunodeficiency after HSC transplantation?

Answer 90

🔹 Immunosuppression from pre-transplant treatments (chemotherapy/radiation) 🔹 Delayed repopulation of the immune system 🔹 Infection risk: Particularly CMV reactivation, leading to CMV pneumonitis, which can be fatal

Question 90

💉 What is the role of graft-versus-leukemia (GVL)?

Answer 90

🔹 Graft-versus-leukemia effect is beneficial in leukemia cases 🔹 Allogeneic T cells can help eliminate leukemic cells 🔹 Induction of GVL: Infusion of donor T cells to treat relapsed chronic myeloid leukemia

Question 90

What are Immunodeficiency Diseases?

Answer 90

Definition: Immunodeficiency diseases occur when the immune system is impaired, making individuals more susceptible to infections. Types: Primary (Congenital): Genetic defects affecting innate immunity or adaptive immunity (B and T lymphocytes). Secondary (Acquired): Caused by cancer, infections, malnutrition, or side effects of treatments like chemotherapy. Clinical Manifestation: Increased susceptibility to infections, including newly acquired or reactivation of latent infections.

Question 90

Primary Immunodeficiencies

Answer 90

Cause: Genetic defects affecting immune cells (e.g., leukocytes, complement system) or immune responses (e.g., B/T lymphocytes). Detection: Often diagnosed in infancy (6 months to 2 years) due to recurrent infections.

Question 90

Defects in Innate Immunity

Answer 90

Leukocyte Function Defects: 1- Leukocyte Adhesion Deficiency (LAD): Defect in leukocyte adhesion to blood vessels, leading to recurrent bacterial infections. LAD Type 1: β2 chain defect in integrins. LAD Type 2: Absence of sialyl-Lewis X. 2- Phagolysosome Function Defects: Chédiak-Higashi Syndrome: Defective phagosome-lysosome fusion, leading to neutropenia, recurrent infections, and abnormalities in melanocytes and nerve cells. 3- Microbicidal Activity Defects: Chronic Granulomatous Disease (CGD): Defects in phagocyte oxidase, leading to defective bacterial killing and granuloma formation. 4- Defects in TLR Signaling: TLR3 Defect: Recurrent herpes simplex encephalitis. MyD88 Defect: Increased susceptibility to bacterial pneumonias.

Question 91

What are Complement System Deficiencies?

Answer 91

C2 Deficiency: Most Common Complement deficiency. Clinical Manifestations: Increased susceptibility to bacterial and viral infections. Autoimmune: SLE-like disease in some patients. C3 Deficiency: Clinical Manifestations: Serious, recurrent pyogenic infections (pus-producing), and increased risk of immune complex-mediated glomerulonephritis (kidney inflammation). C5-C9 Deficiency (Terminal Components): Clinical Manifestations: Increased susceptibility to Neisseria infections (gonorrhea, meningitis). Reason: Neisseria bacteria are vulnerable to complement-mediated lysis. Mannose-Binding Lectin Deficiency: Clinical Manifestations: Increased risk of infections due to impaired initiation of the lectin pathway of complement.

Question 91

Deficiency of Complement Regulators

Answer 91

C1 Inhibitor (C1 INH) Deficiency: Disorder: Hereditary Angioedema (autosomal dominant). Clinical Manifestations: Episodes of swelling (edema) in skin and mucosal areas, including the larynx and gastrointestinal tract, which may cause asphyxia, nausea, vomiting, and diarrhea. Trigger: Minor trauma or emotional stress. Treatment: C1 inhibitor concentrates from human plasma. Paroxysmal Nocturnal Hemoglobinuria (PNH): Cause: Deficiency of complement regulatory proteins. Clinical Manifestation: Hemolysis (destruction of red blood cells), leading to anemia, thrombosis, and organ damage. Other Diseases: Chronic Hemolytic Uremic Syndrome (HUS). Age-Related Macular Degeneration.

Question 91

Severe Combined Immunodeficiency (SCID)

Answer 91

SCID involves defects in both humoral (B-cell) and cell-mediated (T-cell) immune responses. Clinical Features: Thrush (oral candidiasis) and diaper rash in infancy. Failure to thrive. Severe, recurrent infections (e.g., Candida albicans, Pneumocystis jirovecii). Graft-versus-host disease (GVHD) due to maternal T cells attacking the fetus. 💡 Genetic Forms: X-linked SCID: Mutation: Common γ-chain (γc) of cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21). Key Effects: Deficient T-cell and NK cell function. B-cells may be normal, but antibody synthesis is impaired due to lack of T-cell help. Autosomal Recessive SCID: Most Common Cause: Adenosine deaminase (ADA) deficiency. Mechanism: Accumulation of toxic metabolites (e.g., deoxy-ATP) damages T-cells more than B-cells. Other Causes: Mutations in RAG genes (essential for gene rearrangement in TCR and Ig). Mutations in JAK3 (important for cytokine receptor signaling). Defects in signaling molecules and calcium channels.

Question 92

Histologic Findings in SCID:

Answer 92

Thymus: Small and devoid of lymphoid cells. In X-linked SCID, thymus shows undifferentiated epithelial cells. In ADA deficiency, remnants of Hassall's corpuscles. Lymphoid Tissues: Hypoplastic, with depletion of T-cell areas and sometimes both T-cell and B-cell zones.

Question 92

Treatment of SCID

Answer 92

Hematopoietic Stem Cell (HSC) Transplantation: Main treatment. Gene Therapy: Successful in X-linked SCID by introducing a normal γc gene using viral vectors. Risks: Some patients developed T-cell lymphoblastic leukemia due to oncogene activation.

Question 92

What is X-linked agammaglobulinemia, and what are its key features?

Answer 92

Cause: Mutations in Bruton tyrosine kinase (BTK), a cytoplasmic tyrosine kinase crucial for B-cell maturation. Genetics: X-linked, mostly affecting males; females may be affected in rare cases. Immunologic Defect: Failure of B-cell precursors (pre–B and pro–B cells) to develop into mature B cells due to a failure in the pre-B cell receptor (pre-BCR) signaling.

Question 92

Clincial features of Bruton agammaglobulinemia

Answer 92

Recurrent bacterial infections 🦠 (e.g., pharyngitis, otitis media, pneumonia) caused by Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus. Viral infections 🔴 (e.g., enteroviruses like polio, echovirus → paralytic poliomyelitis, fatal encephalitis). Absence or low B cells in circulation ❌ and decreased immunoglobulins (IgA, IgG, IgM). Underdeveloped germinal centers 🏚️ in lymphoid tissues (e.g., tonsils, lymph nodes). Normal T-cell function 🤝, but no plasma cells. Autoimmune diseases (30% of patients) 🦠 (e.g., arthritis, dermatomyositis) due to loss of self-tolerance. Failure to thrive due to persistent infections and lack of functional antibodies. 🚨

Question 92

What is DiGeorge Syndrome, and what is its cause?

Answer 92

➡️ DiGeorge Syndrome is a T-cell deficiency caused by failure of the thymus to develop, resulting from abnormal development of the 3rd and 4th pharyngeal pouches. This leads to: 🟠 T-cell deficiency 🟠 Tetany (due to parathyroid deficiency) 🟠 Congenital heart and great vessel defects 🟠 Facial abnormalities (e.g., mouth and ear changes)

Question 92

What are the immune system-related manifestations of DiGeorge Syndrome?

Answer 92

➡️ Affected individuals have: 🟠 Low T lymphocytes → Deficient T-cell mediated immunity 🟠 Poor defense against fungal and viral infections 🟠 T-cell zones (in lymph nodes and spleen) are depleted 🟠 Ig levels may be normal or reduced ⚠️ Common infections: Fungal (e.g., Candida) and viral (e.g., Pneumocystis jirovecii, certain viruses) 🟠 Facial abnormalities: Abnormal appearance of the mouth, ears, and face

Question 92

❓ What is the genetic cause of DiGeorge Syndrome?

Answer 92

➡️ DiGeorge Syndrome is primarily caused by a 22q11 deletion, with a deletion of the TBX1 gene, which is essential for development of branchial arches and the great vessels. 🟠 This gene loss results in: 🟠 Thymic hypoplasia, leading to T-cell deficiency

Question 93

What are the clinical manifestations of DiGeorge Syndrome?

Answer 93

🟠 Tetany (from parathyroid hypoplasia) 🟠 Congenital heart defects: e.g., tetralogy of Fallot 🟠 Cleft palate, hypoparathyroidism, and abnormal facies 🟠 Low T-cell counts → Vulnerability to infections (fungal, viral, and bacterial) 🟠 Cardiac abnormalities: Tetralogy of Fallot, interrupted aortic arch, etc.

Question 93

How is DiGeorge Syndrome diagnosed and treated?

Answer 93

➡️ Diagnosis: 🟠 Genetic testing reveals the 22q11 deletion 🟠 FISH (Fluorescence In Situ Hybridization) used to confirm deletion ➡️ Treatment: 🟠 Thymus transplantation or T-cell replacement therapy for immune support 🟠 Calcium and vitamin D supplementation for tetany (due to hypoparathyroidism) 🟠 Surgical intervention for congenital heart defects

Question 93

What is Hyper-IgM Syndrome, and what causes it?

Answer 93

➡️ Hyper-IgM Syndrome is a disorder where patients have: 🟠 Normal IgM levels but deficient IgG, IgA, and IgE antibodies 🟠 Caused by defects in CD4+ helper T cells or intrinsic B-cell defects 🟠 Most common cause: Mutations in the CD40L gene (X-linked) 🟠 Autosomal recessive form: Defects in CD40 or AID (Activation-induced cytidine deaminase)

Question 93

What are the clinical manifestations of Hyper-IgM Syndrome? ➡️ Patients typically present with:

Answer 93

➡️ Patients typically present with: 🟠 Recurrent pyogenic infections (e.g., pneumonia, otitis media) 🟠 Failure to class-switch antibodies → Impaired immune response 🟠 Susceptibility to Pneumocystis jirovecii pneumonia (due to CD40L-mediated macrophage dysfunction) 🟠 Autoimmune issues: Autoimmune hemolytic anemia, thrombocytopenia, neutropenia 🟠 IgM-producing plasma cells proliferate in the gastrointestinal tract, causing inflammation

Question 94

How is Hyper-IgM Syndrome diagnosed and treated?

Answer 94

➡️ Diagnosis: 🟠 Serum Ig levels: Normal IgM, low IgG, IgA, and IgE 🟠 Flow cytometry for CD40L and CD40 mutations ➡️ Treatment: 🟠 Ig replacement therapy (IVIG) 🟠 Prophylactic antimicrobials for infection prevention 🟠 Bone marrow transplant in severe cases

Question 95

What is Common Variable Immunodeficiency (CVID), and how is it characterized?

Answer 95

➡️ CVID is a heterogeneous disorder characterized by: 🟠 Hypogammaglobulinemia (low levels of antibodies) 🟠 Affects all antibody classes or sometimes just IgG 🟠 Can be sporadic or familial (inheritance patterns are diverse)

Question 95

What are the immune system-related features of CVID?

Answer 95

➡️ Key features of CVID: 🟠 Normal or near-normal B cell numbers, but impaired differentiation into plasma cells 🟠 Defective helper T cell-mediated activation of B cells 🟠 Abnormalities in BAFF receptors or ICOS molecules (promotes B cell survival and differentiation) 🟠 Selective IgA deficiency is common among family members

Question 96

What are the clinical manifestations of Common Variable Immunodeficiency?

Answer 96

➡️ Clinical features: 🟠 Recurrent infections: Sinopulmonary infections (bacterial) 🟠 Herpesvirus infections (e.g., Epstein-Barr Virus) 🟠 Enterovirus infections, causing meningoencephalitis 🟠 Chronic diarrhea (e.g., Giardia lamblia) 🟠 Increased risk of autoimmune diseases (rheumatoid arthritis, etc.) 🟠 Lymphoid malignancies: Increased risk, particularly gastric cancer

Question 97

How is CVID diagnosed and treated?

Answer 97

➡️ Diagnosis: 🟠 Exclusion of other causes of decreased antibody production 🟠 Low serum immunoglobulins (IgG, IgA, IgM) 🟠 Normal or near-normal B cell count ➡️ Treatment: 🟠 Ig replacement therapy (IVIG or subcutaneous Ig) 🟠 Prophylactic antibiotics to prevent infections 🟠 Vaccinations for infection prevention

Question 97

What is Isolated IgA Deficiency?

Answer 97

🔹 Definition: Impaired differentiation of naïve B cells to IgA-producing plasma cells. 🔹 Prevalence: 1 in 600 in individuals of European descent. Less common in African and Asian populations. 🔹 Cause: Unknown in most cases; defects in the BAFF receptor described in some. 🔹 Clinical Features: 🏥 Asymptomatic: Many cases show no symptoms. 🌬️ Infections: Mucosal defenses weakened → recurrent respiratory, gastrointestinal, and urogenital infections. 😷 Autoimmunity & Allergies: Higher incidence of SLE, rheumatoid arthritis, and respiratory allergies. 💉 Blood Transfusions: Risk of severe anaphylaxis if transfused with blood containing normal IgA. 🔹 Management: No specific treatment for IgA deficiency itself. Symptom management as needed.

Question 98

What is X-Linked Lymphoproliferative Disease (XLP)?

Answer 98

🔹 Cause: Mutations in SAP (SLAM-associated protein) → impaired NK, T-cell activation, and inability to eliminate EBV. 🔹 Clinical Features: 🦠 EBV Infection: Severe, often fatal infectious mononucleosis. 💉 B-cell Tumors: Increased risk of developing B-cell tumors. 🔬 Other Issues: Impaired development of germinal centers and high-affinity antibodies. 🔹 Inheritance: X-linked, affecting males more severely. 🔹 Management: Antiviral treatments may help manage infections.

Question 99

What are Other Defects in Lymphocyte Activation?

Answer 99

🔹 Mendelian Susceptibility to Mycobacterial Disease (MSMD): 🦠 Cause: Mutations affecting Th1 response → increased susceptibility to mycobacterial infections. 🔬 Symptoms: Recurrent mycobacterial infections. 🔹 Job Syndrome (Hyper-IgE Syndrome): 🌸 Cause: Defective Th17 responses → chronic mucocutaneous candidiasis and bacterial skin infections. 🔬 Symptoms: Recurrent fungal and bacterial skin infections, high IgE levels.

Question 100

🧬 What is Wiskott-Aldrich Syndrome (WAS)?

Answer 100

🔹 Cause: X-linked mutations in the WASP gene (Xp11.23) → defects in T cell activation and cytoskeletal structure. 🔹 Clinical Features: ⚠️ Triad: Thrombocytopenia, eczema, recurrent infections. 🩸 Immunodeficiency: Loss of T lymphocytes in peripheral blood and T-cell zones of lymph nodes. 🧬 Immunoglobulin Levels: Low IgM, normal IgG, elevated IgA and IgE. 💉 Cancer Risk: Increased risk of B-cell lymphoma. 🔹 Management: Hematopoietic stem cell transplantation (HSC) is the primary treatment.

Question 100

🔬 What is Ataxia Telangiectasia (AT)?

Answer 100

🔹 Cause: Autosomal-recessive mutations in the ATM gene (chromosome 11). 🔹 Clinical Features: 🧠 Neurologic Symptoms: Abnormal gait (ataxia), telangiectases (vascular malformations). 🦠 Immunodeficiency: Defective isotype-switched antibodies (IgA, IgG2), thymic hypoplasia. 🩺 Infections: Recurrent upper/lower respiratory infections. 🧬 Increased Cancer Risk: High incidence of lymphomas and other cancers. 🔬 DNA Repair Defect: Impaired V(D)J recombination and Ig isotype switching. 🔹 Management: Symptomatic treatment and cancer monitoring.

Question 100

What is Acquired Immunodeficiency Syndrome (AIDS)?

Answer 100

🔹 Cause: Human immunodeficiency virus (HIV), a retrovirus. 🔹 Pathogenesis: Profound immunosuppression → increased susceptibility to opportunistic infections, secondary neoplasms, and neurologic manifestations.

Question 100

🧬 What Are the Key Mechanisms of HIV Transmission?

Answer 100

🔹 Sexual Transmission: Dominant mode (75% worldwide). HIV carried in semen, transmitted through mucosal trauma (oral/rectal). 🔹 Parenteral Transmission: Sharing needles, contaminated blood products. 🔹 Co-factors: Sexually transmitted diseases (STDs), particularly syphilis, chancroid, and herpes, increase transmission risk.

Question 101

Pathogenesis of HIV

Answer 101

Immune System Target: 🔹 Primary Target: CD4+ T cells, macrophages, DCs. 🔹 Deficiency: Loss of CD4+ T cells → weak immunity. Viral Replication: 🔹 Entry: HIV infects T cells, macrophages, DCs via mucosal tissues. 🔹 Latent Phase: Virus can stay latent in lymphoid tissues.

Question 101

Mechanism of T-Cell Depletion in HIV:

Answer 101

Direct Killing by Virus 🔹 Viral Replication: 100 billion new viral particles daily, leading to 1-2 billion CD4+ T cell deaths. 🔹 Tissue Damage: Virus primarily infects tissues, leading to significant T-cell loss. Additional Mechanisms: 🔹 Chronic Activation: Apoptosis from activation-induced cell death. 🔹 Pyroptosis: Inflammasome activation → inflammatory cytokines. 🔹 Syncytia Formation: Infected and uninfected T cells fuse, causing cell death. 🔹 Thymic Dysfunction: Loss of CD4+ T-cell precursors. 🔹 Qualitative T-cell Defects: Reduced T-cell proliferation, Th1 responses, and memory cell function.

Question 101

HIV Infection of Non-T Cells

Answer 101

🔹 Infection & Persistence: Can replicate virus, resist cytopathicity, and serve as viral reservoirs. 🔹 Role as Portals: M-tropic strains infect macrophages, spreading virus. 🔹 Functional Defects: Impaired immune response and antigen presentation. Dendritic Cells (DCs) 🔹 Mucosal & Follicular DCs: Important in transmission and maintenance of HIV. 🔹 FDCs as Reservoirs: Trap HIV-coated antibodies, retaining infectivity.

Question 101

💉 B-Cell Function in HIV

Answer 101

Early B-cell Activation: 🔹 Polyclonal Activation: Leads to hypergammaglobulinemia and autoimmunity (e.g., immune thrombocytopenic purpura). 🔹 EBV & IL-6: Both stimulate B-cell proliferation. Impaired Immunity: 🔹 Defective Antibody Response: Inability to respond to new infections. 🔹 Susceptibility to Infections: Increased risk for encapsulated bacterial infections like S. pneumoniae.

Question 101

What is the primary cause of neurologic manifestations in HIV infection

Answer 101

The clinical syndrome of HIV-associated neurocognitive disorder (HAND) is mainly caused by microglia, the predominant brain cells infected by HIV. Infection occurs via T cells or monocytes, which carry the virus into the brain. Most neurologic damage is indirect, resulting from viral products and soluble factors like IL-1, TNF, IL-6, and nitric oxide produced by infected microglia

Question 102

How does HIV enter the brain and cause CNS damage?

Answer 102

IV is carried into the brain by infected T cells or monocytes. Although neurons are not infected, they may be indirectly damaged by soluble factors like gp120 (direct damage to neurons) and inflammatory cytokines produced by infected microglia. This results in neurocognitive impairments seen in HAND.

Question 103

What phases are involved in the natural history of HIV infection?

Answer 103

Acute Retroviral Syndrome (early infection with flu-like symptoms) Chronic Phase/Clinical Latency (asymptomatic phase) AIDS (severe immunodeficiency, marked by opportunistic infections). ⚡

Question 103

What happens during the acute retroviral syndrome in HIV infection?

Answer 103

Answer: The acute phase occurs 3 to 6 weeks after infection and is marked by a flu-like syndrome (fever, sore throat, myalgias, rash). Viral replication occurs in mucosal tissues, leading to viremia. This is followed by the development of CD8+ T cells that help control the virus temporarily. Viral load drops to a steady-state level (viral set point).

Question 103

How does viral load influence the progression of HIV?

Answer 103

Viral load is a critical marker of HIV progression. A higher viral load (>36,270 copies/mL) is associated with faster progression to AIDS, while a lower load (<4350 copies/mL) correlates with slower progression. The viral set point reflects this equilibrium and helps predict the rate of CD4+ T-cell decline

Question 103

What is the role of CD4+ T cells during the chronic phase of HIV infection?

Answer 103

In the chronic phase, CD4+ T cells are continually lost within lymphoid tissues (spleen, lymph nodes) despite the absence of overt symptoms. The loss is compensated early, but eventually T-cell depletion surpasses the rate of replacement, leading to immunodeficiency.

Question 103

What clinical symptoms appear during the chronic phase of HIV infection?

Answer 103

During chronic infection, patients may be asymptomatic or develop minor opportunistic infections like oral thrush, vaginal candidiasis, herpes zoster, and sometimes tuberculosis. There may also be autoimmune thrombocytopenia. 🔍

Question 103

What is the significance of CXCR4 and CCR5 coreceptor switching in HIV infection?

Answer 103

Coreceptor switching occurs when HIV evolves to use CXCR4 (in addition to or instead of CCR5) for entry into target cells. This shift typically correlates with more rapid decline in CD4+ T cells and faster progression to AIDS.

Question 103

How does HIV avoid immune detection during the chronic phase?

Answer 103

IV evades immune detection by destroying CD4+ T cells, using antigenic variation, and down-regulating MHC Class I molecules on infected cells, which prevents recognition by CD8+ cytotoxic T lymphocytes (CTLs)

Question 103

What are the key stages in the natural history of HIV infection?

Answer 103

Primary Infection: Virus enters via mucosal epithelia, infecting memory CD4+ T cells. Leads to acute retroviral syndrome (fever, sore throat, myalgias, rash). Chronic Phase: Asymptomatic with steady-state viremia and CD4+ T-cell decline. Viral load and CD4+ count predict disease progression. AIDS: Severe immunosuppression leads to opportunistic infections and secondary neoplasms (e.g., pneumonia, tuberculosis, candidiasis).

Question 104

What are the key characteristics of AIDS?

Answer 104

Clinical Manifestations: Fever, weight loss, diarrhea, generalized lymphadenopathy, opportunistic infections (e.g., Pneumocystis jirovecii, CMV, cryptococcosis), neurologic disease (e.g., progressive multifocal leukoencephalopathy), and secondary cancers (Kaposi's sarcoma). Opportunistic Infections: Candidiasis, cytomegalovirus (CMV) retinitis, mycobacterium infections (including tuberculosis), toxoplasmosis, and cryptosporidiosis.

Question 104

What are long-term nonprogressors and elite controllers in HIV?

Answer 104

Long-term Nonprogressors: Asymptomatic for >10 years with stable CD4+ counts and low viral load. Elite Controllers: <50 RNA copies/mL, showing robust immune response, but viral evolution still ongoing.

Question 104

What are the main causes of death in untreated AIDS patients?

Answer 104

Opportunistic infections like Pneumocystis jirovecii pneumonia, tuberculosis, cryptococcosis, toxoplasmosis, and CMV. Secondary neoplasms: Kaposi's sarcoma, non-Hodgkin lymphoma.

Question 104

What are the common tumors associated with AIDS?

Answer 104

🦠 Kaposi Sarcoma (KS): Most common tumor in AIDS, caused by HHV-8. Common in sub-Saharan Africa. Declined in the US due to ART. Features: vascular tumors with spindle-shaped cells, angiogenesis, and chronic inflammation. 💥 B-cell Lymphomas: Increased in AIDS due to EBV infection and T-cell immunodeficiency. Often aggressive and extranodal (e.g., CNS, gut). 💔 Cervical & Anal Cancer: Caused by HPV. Increased risk in HIV-infected individuals with low CD4 counts, particularly in women and men who have sex with men

Question 104

What is Kaposi Sarcoma (KS) in AIDS and its pathogenesis?

Answer 104

🔬 HHV-8 infection causes KS, leading to spindle cell proliferation and angiogenesis. AIDS-related KS: More aggressive and widespread (skin, mucous membranes, GI tract, lymph nodes, lungs). 🧬 Pathogenesis: HHV-8 infection is necessary but not sufficient. HIV immunosuppression aids in HHV-8 dissemination.

Question 104

What is the impact of AIDS on the central nervous system (CNS)?

Answer 104

🧠 Neurologic Manifestations: Seen in 40-60% of HIV patients clinically; 90% at autopsy. Can be the first symptom of HIV infection. Types of CNS Involvement: 🔄 Meningoencephalitis (self-limited at seroconversion) 🧠 Aseptic Meningitis 💀 Vacuolar Myelopathy 🦵 Peripheral Neuropathies 🧠 HIV-associated Neurocognitive Disorder (HAND): Progressive encephalopathy linked to microglial infection and immune response.

Question 104

How does Antiretroviral Therapy (ART) affect HIV progression?

Answer 104

💊 ART Impact: Combination of drugs targeting reverse transcriptase, protease, and integrase. 🧬 Reduces HIV viral load (<50 copies RNA/mL). 🦠 Prevents drug-resistant mutants. 🚫 Reduces AIDS-related mortality: Decreased from 16-18 per 100,000 (1995-96) to <4 per 100,000. 🧑‍👩‍👧‍👦 Reduces transmission, especially from mother to child. 📉 Immune Recovery: CD4+ T-cell count increases over years, leading to immune system recovery.

Question 104

What complications arise from long-term ART use?

Answer 104

⚠️ Immune Reconstitution Inflammatory Syndrome (IRIS): Paradoxical worsening despite viral suppression; poorly understood immune response. 💥 Adverse Effects: 🐏 Lipoatrophy (loss of fat, especially facial) 💪 Lipoaccumulation (central fat deposition) ⚡ Metabolic Issues: Elevated lipids, insulin resistance, cardiovascular, renal, and liver problems. 🦠 Non-AIDS Morbidity: Cancers, accelerated cardiovascular, kidney, liver disease more common than classic AIDS complications

Question 104

What are the morphologic features of HIV-related tissue changes?

Answer 104

🧬 Lymphoid Hyperplasia: Early stages show enlarged B-cell follicles with serpiginous shapes. ⚡ Lymphoid Involution: Later stages show depleted lymph nodes and disrupted germinal centers, with macrophages often housing opportunistic pathogens. 💔 Organ Wasteland: Spleen and thymus become devoid of lymphocytes in later stages. 🔬 Inflammatory Responses: T-cell deficiency leads to atypical responses (e.g., no granuloma formation with mycobacteria).

Question 104

What is amyloidosis, and what causes it?

Answer 104

Amyloidosis involves extracellular deposition of misfolded proteins that form fibrillar aggregates, causing tissue damage and functional impairment. These proteins are soluble in their normal folded form but aggregate into insoluble fibrils, leading to amyloid deposits in tissues. Amyloid deposits bind to proteoglycans and glycosaminoglycans, including heparan sulfate and dermatan sulfate, and serum amyloid P.

Question 104

What are the main types of amyloid proteins?

Answer 104

Amyloid Light Chain (AL): Derived from immunoglobulin light chains secreted by monoclonal plasma cells, associated with plasma cell tumors. Amyloid-Associated (AA): Derived from SAA (serum amyloid-associated) protein, produced by the liver during chronic inflammation, also known as secondary amyloidosis. β-Amyloid (Aβ): Found in Alzheimer's disease as part of cerebral plaques and deposits in blood vessels in the brain.

Question 105

What are some less common forms of amyloid proteins?

Answer 105

Transthyretin (TTR): Found in familial amyloid polyneuropathies and as senile systemic amyloidosis in elderly individuals, also in the heart. β2-microglobulin: Found in patients on long-term hemodialysis, depositing around joints or soft tissues. Prion proteins: In prion diseases, misfolded prions aggregate and acquire amyloid characteristics in the CNS.

Question 105

What is the pathogenesis of amyloidosis?

Answer 105

Amyloidosis results from misfolded proteins becoming insoluble, aggregating, and depositing as fibrils in extracellular tissues. Normally, misfolded proteins are degraded by proteasomes or macrophages. In amyloidosis, these quality-control mechanisms fail, causing the accumulation of misfolded proteins outside cells.

Question 105

What are the two main categories of proteins involved in amyloidosis?

Answer 105

1️⃣ Normal proteins: Have an inherent tendency to misfold and form fibrils when produced in increased amounts. 2️⃣ Mutant proteins: Prone to misfolding and aggregation due to genetic mutations.

Question 105

How is amyloidosis clinically classified?

Answer 105

Amyloidosis can be systemic (generalized) or localized (e.g., heart). Systemic amyloidosis is subclassified into: 🔹 Primary amyloidosis (associated with plasma cell proliferations) 🔹 Secondary amyloidosis (complicates chronic inflammatory processes) 🔹 Hereditary/familial amyloidosis (genetically determined patterns of organ involvement)

Question 105

What is primary amyloidosis, and how is it related to plasma cell disorders?

Answer 105

Primary amyloidosis is often systemic and associated with AL amyloid. It is caused by a clonal proliferation of plasma cells producing Ig light chains prone to amyloid formation. It is seen in multiple myeloma (a plasma-cell tumor) but can also occur without overt B-cell neoplasms, manifesting as monoclonal gammopathy.

Question 105

What is reactive (secondary) systemic amyloidosis, and what conditions are associated with it?

Answer 105

Reactive systemic amyloidosis involves AA amyloid deposits and is secondary to chronic inflammatory conditions. Commonly associated with: 🔹 Rheumatoid arthritis 🔹 Ankylosing spondylitis 🔹 Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) 🔹 Heroin use (due to chronic skin infections) 🔹 Solid tumors (e.g., renal cell carcinoma, Hodgkin lymphoma)

Question 105

How does the AA amyloid deposition occur in reactive amyloidosis?

Answer 105

SAA (serum amyloid-associated) protein is produced by the liver in response to inflammation. Cytokines like IL-6 and IL-1 stimulate SAA synthesis during inflammation. Amyloid deposition occurs when SAA is not adequately degraded due to an enzyme defect or genetic abnormalities in SAA structure, leading to its accumulation as insoluble AA fibrils.

Question 105

What is familial Mediterranean fever, and how is it related to amyloidosis?

Answer 105

Familial Mediterranean fever is an autosomal recessive autoinflammatory syndrome. It causes excessive production of IL-1 in response to inflammatory stimuli. Characterized by attacks of fever and inflammation of serosal surfaces (peritoneum, pleura, synovial membrane). It is associated with amyloidosis due to increased SAA production, which forms AA amyloid fibrils.

Question 105

What are familial amyloidotic polyneuropathies, and what protein is involved?

Answer 105

These are autosomal dominant disorders characterized by amyloid deposition primarily in peripheral and autonomic nerves. The amyloid fibrils are composed of mutant TTR (transthyretin), which misfolds and aggregates due to genetic mutations, making it resistant to degradation.

Question 106

What is hemodialysis-associated amyloidosis, and how does it develop?

Answer 106

Hemodialysis-associated amyloidosis occurs in long-term hemodialysis patients due to β2-microglobulin deposition. β2-microglobulin accumulates in the serum of patients with renal failure and is not filtered by dialysis membranes, leading to deposition in joints, muscles, tendons, and ligaments. Carpal tunnel syndrome is a common presentation. With newer dialysis filters, the incidence of this complication has decreased.

Question 106

What is localized amyloidosis, and where is it commonly found?

Answer 106

Localized amyloidosis involves amyloid deposits restricted to a single organ or tissue. Commonly found in: 🔹 Lung 🔹 Eye These deposits can be either grossly visible nodules or detected microscopically. In some cases, AL amyloid (from plasma cell production) may be present.

Question 106

How does endocrine amyloid present, and where is it commonly found?

Answer 106

Endocrine amyloid deposits may be found in tumors such as: 🔹 Medullary thyroid carcinoma 🔹 Pancreatic islet tumors 🔹 Pheochromocytoma 🔹 Islets of Langerhans (in type 2 diabetes) The amyloid proteins involved are often derived from polypeptide hormones or unique proteins (e.g., islet amyloid polypeptide). In medullary carcinoma, amyloid presence serves as a diagnostic feature.

Question 107

What is senile systemic amyloidosis, and how does it relate to aging?

Answer 107

Senile systemic amyloidosis refers to amyloid deposition seen in elderly patients (usually in their 70s and 80s). The amyloid is derived from normal TTR (transthyretin). Most commonly affects the heart, causing restrictive cardiomyopathy and arrhythmias (previously referred to as senile cardiac amyloidosis).

Question 107

How does the mutant TTR form affect aging-related amyloidosis?

Answer 107

A mutant form of TTR is associated with cardiac amyloidosis in some elderly individuals. About 4% of African descent individuals in the U.S. express this mutant TTR, leading to cardiomyopathy in both homozygous and heterozygous individuals. The prevalence of clinically manifest cardiac disease in these patients is not well-defined.

Question 107

How does amyloid affect the appearance of organs on gross examination?

Answer 107

When amyloid deposits accumulate in large amounts, the affected organ may become enlarged with a gray, waxy, firm consistency. Macroscopic examination: Amyloid may or may not be visible depending on the amount and organ affected.

Question 107

How does amyloidosis manifest in the kidneys?

Answer 107

Gross appearance: Kidneys may be normal or shrunken (due to ischemia from vascular narrowing). Histology: 🔹 Amyloid deposits are primarily in glomeruli, but also in interstitial tissues, arteries, and arterioles. 🔹 Early deposits cause thickening of the mesangial matrix and widening of basement membranes. 🔹 Advanced stages: Capillary narrowing, obliteration of glomeruli, and large amyloid masses.

Question 107

What are the two patterns of amyloid deposition in the spleen?

Answer 107

Sago spleen: Amyloid is confined to splenic follicles, creating tapioca-like granules on gross inspection. Lardaceous spleen: Amyloid involves the splenic sinuses and red pulp, with large map-like areas of amyloidosi

Question 107

How does amyloidosis affect the liver?

Answer 107

Gross appearance: The liver may be enlarged (hepatomegaly). Histology: 🔹 Amyloid deposits begin in the space of Disse and gradually encroach on hepatic parenchyma and sinusoids. 🔹 Pressure atrophy and disappearance of hepatocytes may occur, with potential total replacement of liver parenchyma. Vascular involvement is common, but liver function is usually preserved.

Question 107

How does amyloidosis manifest in the heart?

Answer 107

Gross appearance: Heart may appear normal or enlarged and firm. Histology: 🔹 Deposits initially accumulate subendocardially and between myocardial fibers. 🔹 Pressure atrophy of myocardial fibers can occur with expansion of amyloid deposits. 🔹 Conduction system damage from subendocardial deposits can cause electrocardiographic abnormalities.

Question 107

What are the common manifestations of amyloidosis in other organs?

Answer 107

Tongue: Nodular amyloid deposits can cause macroglossia (tumor-forming amyloid). Respiratory tract: Amyloidosis can affect the larynx, bronchi, and bronchioles, either focally or diffusely. Brain: Amyloid plaques and blood vessels may show amyloid deposits in Alzheimer's disease. Peripheral and autonomic nerves: Amyloid deposition is a feature of familial amyloidotic neuropathies. Carpal tunnel syndrome: Common in patients with long-term hemodialysis due to amyloid in the wrist ligaments.

Question 108

What are the clinical outcomes of amyloidosis in the kidneys?

Answer 108

Advanced renal involvement: Progressive obliteration of glomeruli leads to renal failure and uremia. Renal failure is a common cause of death in patients with amyloidosis.

Question 108

What are the cardiac manifestations of amyloidosis?

Answer 108

Congestive heart failure may develop insidiously. Conduction disturbances and arrhythmias are the most serious and potentially fatal complications. Occasionally, amyloidosis can present as restrictive cardiomyopathy, mimicking chronic constrictive pericarditis.

Question 108

How does amyloidosis affect the gastrointestinal system?

Answer 108

Gastrointestinal involvement may be asymptomatic or present with: 🔹 Malabsorption, diarrhea, and digestive disturbances. 🔹 Amyloidosis of the tongue may cause enlargement and inelasticity, leading to difficulty with speech and swallowing.

Question 108

What vascular complications can amyloidosis cause?

Answer 108

Vascular fragility due to amyloid deposits can lead to spontaneous bleeding or bleeding following minor trauma. In some cases, AL amyloid binds to and inactivates factor X, causing a life-threatening bleeding disorder.

Question 109

How is amyloidosis diagnosed?

Answer 109

Histologic demonstration of amyloid deposits is required for diagnosis. Common biopsy sites: 🔹 Kidney (if renal symptoms are present), 🔹 Rectal or gingival tissues (if systemic amyloidosis is suspected). Congo red staining of abdominal fat aspirates: Specific but low sensitivity. AL amyloidosis: Perform serum and urine protein electrophoresis and immunoelectrophoresis. 🔹 Bone marrow aspirates may show monoclonal plasmacytosis. Scintigraphy with radiolabeled serum amyloid P component: 🔹 Rapid and specific, reveals extent of amyloidosis, and helps monitor treatment response.

Question 109

What is the prognosis for individuals with amyloidosis?

Answer 109

AL amyloidosis: Median survival of 2 years after diagnosis; poorer prognosis when associated with myeloma. Reactive systemic amyloidosis: Better prognosis, dependent on control of the underlying condition. 🔹 Amyloid resorption can occur after treatment of the underlying disease, but it is rare. New treatments: Drugs targeting protein misfolding and inhibiting fibrillogenesis are being developed, offering hope for better outcomes.

Question 109

What is the primary protein involved in familial Mediterranean fever (FMF), and how does it contribute to amyloidosis?

Answer 109

Primary protein: Pyrin 🔹 Pyrin is involved in regulating inflammation through activation of the inflammasome. Amyloid deposition: 🔹 In FMF, excessive IL-1 secretion leads to increased production of SAA (serum amyloid A), which is converted into AA amyloid fibrils, contributing to amyloidosis. Common populations: FMF is seen primarily in people of Armenian, Sephardic Jewish, and Arabic descent.