Questions and Answers
What is the outcome for a DP T-cell that exhibits high affinity interactions with a thymic epithelial cell's HLA bound to self antigen?
During which stage does a DP T-cell undergo negative selection?
What is the primary site of T-cell maturation?
Which cytokine is crucial for the division of lymphoid progenitors during T-cell development?
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What occurs to a DP T-cell after surviving positive selection and negative selection?
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What percentage of developing T-cells typically do not survive the selection process in the thymus?
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What is the outcome for T-cells that bind self-antigens with high affinity during negative selection?
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Which of the following statements best describes central tolerance?
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Which cells are key in guiding T-cell development within the thymus?
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What distinguishes T-cell development from B-cell development in terms of maturation location?
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What leads to the formation of a pannus in rheumatoid arthritis?
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Which cell types are primarily involved in the inflammatory infiltrate of the pannus?
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What is a consequence of osteoclastic activity in rheumatoid arthritis?
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Ankylosis in rheumatoid arthritis refers to what?
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In what timeframe does the greatest joint damage in rheumatoid arthritis typically occur?
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What is a common characteristic of rheumatoid arthritis (RA)?
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Which genetic factor is implicated in increasing the severity of rheumatoid arthritis?
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How does smoking affect the risk of developing rheumatoid arthritis?
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Which of the following is NOT a common feature of rheumatoid arthritis?
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What is the prevalence of rheumatoid arthritis in the worldwide population?
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What is a significant advantage of selective COX-2 inhibitors over non-selective COX inhibitors?
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What condition is primarily treated by aspirin due to its unique ability?
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Which long-term risk is associated with selective COX-2 inhibitors?
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Which of the following represents a potential severe side effect of COX-inhibitors?
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What is a common theory explaining the increased risk of heart attack associated with NSAIDs?
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What is one of the main organs primarily affected by systemic lupus erythematosus?
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Which autoimmune antibody is specifically associated with systemic lupus erythematosus?
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What genetic factor is associated with systemic lupus erythematosus due to familial clustering?
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Which exogenous factor is known to potentially exacerbate systemic lupus erythematosus?
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What is a significant consequence of the inadequate clearance of apoptotic cells in systemic lupus erythematosus?
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Study Notes
T-cell Development
- Lymphocyte development begins in the bone marrow with stem cells that differentiate into lymphoid progenitors influenced by IL-7.
- T-cells undergo minimal maturation in the bone marrow and move to the thymus for further development.
The Thymus
- The thymus is located above the heart, between the great vessels, and is largest before puberty, shrinking thereafter.
- It is divided into cortex and medulla, where thymic epithelial cells significantly influence T-cell maturation.
T-cell Differentiation in the Thymus
- Precursor T-lymphocytes become fully differentiated T-cells in the thymus by rearranging their T-cell receptors (TCRs).
- Positive selection ensures TCRs that can bind antigens presented via HLA survive, while negative selection eliminates those binding self-antigens with high affinity.
- T-cells express either CD4 or CD8 based on interaction with medullary thymic epithelial cells.
Selection Processes
- Positive Selection: DP T-cells with low to medium affinity for HLA-self antigen survive; those with no interaction do not succeed in TCR arrangement.
- Negative Selection: T-cells with high-affinity TCRs for self-antigens are eliminated, preventing autoimmunity.
Tolerance Mechanisms
- Central tolerance occurs primarily in the thymus through negative selection, involving AIRE gene expression to present a wide range of self-antigens.
- Deficiency in AIRE can lead to autoimmune polyendocrinopathy syndrome (APS).
Peripheral Tolerance
- CD4+ Treg cells develop from interactions with antigen-presenting cells (APCs) in non-inflammatory environments, regulated by TGF-β.
- Tregs can reduce the immune response by limiting IL-2 availability for effector cells.
IgA and Mucosal Immunity
- Mucosal surfaces develop tolerance to commensal bacteria early in life, mediated by secreted IgA, which inhibits invasion without causing inflammation.
- Under healthy conditions, TGF-β promotes IgA class-switching in B-cells, maintaining barrier tolerance.
Spleen Functions
- The spleen is a secondary lymphoid organ that influences immune responses to blood-borne antigens and serves in B-cell maturation.
- White pulp contains T-cells and B-cell-rich follicles, playing key roles in immune activation and antibody production.
B-cell Selection
- B-cells undergo positive selection in the bone marrow, with negative selection occurring in the spleen; self-reactive B-cells are subjected to apoptosis.
- Transitional B-cells (T1) mature into T2 B-cells in the spleen, becoming capable of producing antibodies.
Activation of B-cells
- T-independent B-cells can activate without T-cell help through antigen binding and co-receptor activation, producing antibodies rapidly.
Lymphatic System Basics
- Lymph flow is driven by external fluid pressure, skeletal muscle contractions, and thoracic pressure changes during breathing.
- Lymphatic vessels merge to form lymphatic trunks and ducts, draining into the bloodstream at specific locations.
Summary of Key Genes in Tolerance and Autoimmunity
- IL-2R-alpha: Important for Treg development; linked to diseases like Multiple Sclerosis and Type 1 Diabetes.
- CTLA4: Treg receptor crucial for self-tolerance; associated with conditions such as Type 1 Diabetes and Rheumatoid Arthritis.
Rheumatoid Arthritis (RA) - Overview
- Chronic autoimmune disorder characterized by inflammation of the synovium in joints leading to cartilage destruction.
- Mediated by inflammatory cytokines, macrophages, neutrophils, and self-antigen antibodies.
- Often presents as a relapsing-remitting illness; can have extra-articular manifestations.
- Prevalence ranges from 0.5% to 1% globally; 2-3 times more common in women.
RA - Etiology and Pathogenesis
- Genetic factors account for 20-50% of RA etiology with genes such as CTLA-4, HLA DR1, and PTPN-22 implicated.
- Environmental triggers include smoking (1.5 - 3.5X increased risk) and potential infections.
- Pannus formation involves synovial edema, hyperplasia, and extensive inflammatory cell infiltration.
- Osteoclast activity causes subchondral bone erosion leading to joint dysfunction.
RA - Joint Destruction
- Ankylosis occurs when pannus creates fibrous connections between bones, limiting motion.
- Damage includes cartilage destruction, concurrent bone loss, and damage to joint structures.
- Most joint damage occurs within the first 4-5 years, with younger onset linked to severe disease progression.
RA - Clinical Features
- Articular findings are symmetrical involving primarily small joints (MCP, PIP, MTP) and some large joints (knees, shoulders).
- Inflammatory joint pain results in morning stiffness lasting over one hour, easing with activity.
- Characteristic hand deformities include radial/ulnar deviations and abnormalities like swan neck and boutonniere.
RA - Radiographic Characteristics
- Radiographs reveal juxta-articular osteopenia and bone erosions, narrowing joint spaces due to cartilage loss.
RA - Systemic Manifestations
- Common systemic symptoms include fatigue, weight loss, low-grade fever, and anemia of chronic disease.
- Extra-articular complications may include rheumatoid nodules, pericarditis, pulmonary fibrosis, and increased cardiovascular risk due to systemic inflammation.
RA - Diagnosis
- Diagnosis primarily based on clinical signs; laboratory tests include positive rheumatoid factor (75-80% sensitivity), anti-citrulline antibodies, and elevated C-reactive protein (CRP).
Osteoarthritis (OA) - Pathophysiology
- Characterized by changes to subchondral bone including rebuttressing, sclerosis, and formation of cysts due to cracks allowing synovial fluid infiltration.
- Osteophyte formation results from synovial membrane metaplasia, leading to progressive joint pain.
OA - Clinical Features
- Commonly affects large joints (hip, knee) but can involve small joints of the hands.
- Morning stiffness lasts less than an hour and pain exacerbation may be weather-related.
- Characteristic features include Heberden’s nodes at DIPs and Bouchard’s nodes at PIPs, with no systemic symptoms.
OA - Radiographic Features
- X-rays show narrowed joint spaces, subchondral sclerosis, and peripheral osteophytes.
- Severity on X-ray does not correlate well with pain and disability experienced by patients.
Infectious Arthritis - Overview
- Occurs via hematogenous spread or contiguous infection, risking rapid joint destruction due to limited cartilage regeneration.
- Types include suppurative, mycobacterial, Lyme, and viral arthritis.
Infectious Arthritis - Suppurative
- Triggered by bacterial infections spreading from distant sites; risk factors include immune deficiencies, trauma, and IV drug use.
- Common pathogens include N. gonorrhea, Chlamydia, Staphylococcus, and Streptococcus.
- Characterized by acute pain, swelling, fever, and purulent joint aspiration.
Infectious Arthritis - Complications
- After infection resolution, 50% may experience chronic joint pain; septic arthritis carries high mortality risk (up to 50% with Staph aureus).
Infectious Arthritis - Mycobacterial
- Tuberculosis can lead to chronic monoarticular infections, often stemming from adjacent osteomyelitis or dissemination from visceral sites.
Indications for Use of NSAIDs
- Treat inflammatory joint disorders and osteoarthritis.
- Short-term relief for pain linked to inflammation, such as post-operative pain or dental procedures.
- Effective in managing fever and dysmenorrhea (menstrual pain).
- Only aspirin irreversibly inhibits thromboxane production in platelets, making it unique in preventing platelet aggregation.
COX-Inhibitors
- Most COX-inhibitors inhibit both COX-1 and COX-2 enzymes.
- Selective COX-2 inhibitors (like celecoxib) are less likely to cause gastrointestinal bleeding but have a higher association with heart attacks and strokes.
- NSAIDs can increase heart attack risk due to the inhibition of PGI2 formation.
Gastrointestinal and Renal Toxicity of NSAIDs
- NSAID-induced GI toxicity can be mitigated with antacids or prostaglandin receptor activators (e.g., misoprostol).
- Long-term NSAID use can impair renal function; renal function should be evaluated regularly, especially in the elderly.
Glucocorticoids Overview
- Glucocorticoids are anti-inflammatory medications that block phospholipase A2 (PLA2) and inhibit leukocyte migration.
- Used for acute and chronic conditions, they can be administered via inhalation, orally, injected, or topically.
- Long-term use affects the anterior pituitary by decreasing ACTH, leading to adrenal cortex atrophy; requires gradual withdrawal.
Adverse Effects of Glucocorticoids
- Serious side effects include immunosuppression, delayed wound healing, gastrointestinal ulcers, muscle weakness, fat redistribution, hyperlipidemia, and hyperglycemia.
- Neurologic effects can include irritability and psychosis.
- Bone effects involve decreased bone formation and increased resorption, impacting calcium metabolism and growth in children.
Management of Glucocorticoid Withdrawal
- It's critical to taper off glucocorticoids slowly to prevent adrenal crisis in patients who've been on high doses for extended periods.
- Local glucocorticoids typically exhibit fewer systemic side effects.
Vaccination Concepts
- Passive immunization involves transferring antibodies without eliciting a host immune response; immunity fades after weeks to months.
- Active immunization generates memory cells through exposure to weakened microbes or components.
Vaccine Types
- Toxoids stimulate immunity against bacterial toxins; subunit vaccines target bacterial coat components to enhance phagocytosis.
- Conjugate vaccines combine weakly immunogenic proteins with strongly immunogenic ones to generate a better immune response.
Vaccine Enhancement Strategies
- Adjuvants, like aluminum salts, improve immune responses by providing slow release and recruiting antigen-presenting cells (APCs).
Future Vaccine Development
- Current vaccines may not effectively stimulate T-cell responses; research includes improved delivery methods such as liposomes and recombinant vector vaccines.
- mRNA vaccines involve introducing mRNA to APCs, which then produce viral protein to stimulate an immune response.
mRNA Vaccines
- mRNA is sequenced and encased in a protective vehicle for delivery to immune cells.
- This method promotes robust activation of helper T-cells and B-cells, enhancing overall immune response compared to traditional vaccination approaches.
Systemic Lupus Erythematosus (SLE)
- Known as "the disease of 1000 faces" due to its diverse presentations.
- Affects various organs, primarily skin, joints, kidneys, and serosal membranes.
- Prevalence of approximately 1 in 2500; onset typically in 20s and 30s.
- Female-to-male ratio of about 9:1, closer to 2:1 in extremes of age.
- Higher prevalence in individuals of Hispanic and African heritage.
SLE - Pathogenesis and Etiology
- Autoimmune disorder marked by numerous autoantibodies, especially anti-nuclear antibodies (ANA).
- Specific ANAs include anti-ds DNA and anti-Smith antigen antibodies.
- Genetic predisposition indicated by 24% monozygotic twin concordance and notable HLA associations (DR3, A1, B8).
- Environmental triggers include certain drugs, UV exposure, and estrogen.
SLE - Immune Mechanisms
- Failure of self-tolerance leads to activation of CD4+ T cells and self-reactive B cells.
- Type I interferons may contribute to self-tissue damage through TLR activation.
- Ineffective clearance of self-antigens due to deficient C1q impairs macrophages’ ability to remove apoptotic cells.
SLE - Tissue Damage Mechanisms
- Autoantibodies mediate immune complex damage, particularly in renal glomeruli, leading to various hypersensitivity responses.
- Involvement of small blood vessels results in acute necrotizing vasculitis.
SLE - Clinical Features
- Hematological issues include anemia and thrombocytopenia.
- Joint inflammation is common but does not typically erode cartilage.
- Skin manifestations often worsen with sunlight; includes malar rash, urticaria, and bullae.
- Cardiovascular complications may involve myocarditis and valvular damage with increased atherosclerosis.
- Neurological symptoms can include cognitive impairment and seizures; splenomegaly may occur.
- Renal complications involve immune complex deposition, a major contributor to morbidity.
Discoid Lupus
- Primarily skin manifestations with limited systemic involvement; characterized by plaques with diverse features.
SLE - Clinical Course
- Highly variable progression, often involving remissions and flares.
- Common complications include skin and hematologic issues, with renal failure and infections being more serious.
- 10-year survival rate approaches 80%; leading causes of death include renal failure, infection, and coronary artery disease.
Seronegative Spondyloarthropathies
- Defined by the absence of serum markers like Rheumatoid Factor and ANA.
- Strong association with HLA-B27, commonly results in inflammatory back pain.
- Includes conditions such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and arthritis associated with inflammatory bowel disease (IBD).
Ankylosing Spondylitis
- Most prevalent spondyloarthropathy, characterized by fusion (ankylosis) of joints, especially sacroiliac and intervertebral.
- Prevalence ranges from 0.1% to 1%, significantly more common in Caucasians; 2-3 times more frequent in males.
- HLA-B27 presence is a major risk factor; pathological findings include chronic inflammation, joint erosion, and ossification.
Clinical Findings in Ankylosing Spondylitis
- Insidious onset of low back pain in individuals under 40, with symptoms lasting over 3 months.
- Morning stiffness and inactivity intolerance (gelling) with symptomatic relief from exercise.
- Extra-articular symptoms can include acute uveitis and aortitis.
Reactive Arthritis
- Two varieties: post-urethritis and enteritis-associated.
- Commonly linked to HLA-B27 and affects primarily men.
- Pathology includes synovitis leading to serious joint degradation and ossification at insertion sites.
Clinical Features of Reactive Arthritis
- Symptoms typically arise 2-6 weeks post-infection (chlamydial urethritis or gastrointestinal).
- Common joints affected include lower back, ankles, and knees, with occasional chronic progression.
Psoriatic Arthritis
- Present in 5-30% of psoriasis patients; affects both peripheral and axial joints.
- Characterized by dactylitis (sausage fingers) in 20-30% of cases; asymmetric joint involvement is common.
- Extra-articular symptoms are rare, primarily involving conjunctivitis and iritis.
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Explore the intricate process of T-cell development and tolerance in this e-learning quiz for BMS 150. Understand the journey from hematopoietic stem cells to lymphocyte progenitors, influenced by cytokines like IL-7. Test your knowledge and deepen your understanding of lymphocyte development.
