Immunology BMS 150 Week 4

Podcast

Play an AI-generated podcast conversation about this lesson

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?

The DP T-cell differentiates into a regulatory T-cell

The DP T-cell is positively selected

The DP T-cell survives and matures

The DP T-cell undergoes death (correct)

During which stage does a DP T-cell undergo negative selection?

When it successfully binds to foreign antigens

When it has high affinity for self antigens (correct)

When it expresses both CD4 and CD8 co-receptors

When it fails to interact with HLA molecules

What is the primary site of T-cell maturation?

Lymph nodes

Bone marrow

Spleen

Thymus (correct)

Which cytokine is crucial for the division of lymphoid progenitors during T-cell development?

IL-7 Signup and view all the answers

What occurs to a DP T-cell after surviving positive selection and negative selection?

It tests interaction with CD4 or CD8 co-receptors. Signup and view all the answers

What percentage of developing T-cells typically do not survive the selection process in the thymus?

95% Signup and view all the answers

What is the outcome for T-cells that bind self-antigens with high affinity during negative selection?

They do not survive Signup and view all the answers

Which of the following statements best describes central tolerance?

It happens in primary lymphoid organs through negative selection. Signup and view all the answers

Which cells are key in guiding T-cell development within the thymus?

Thymic epithelial cells Signup and view all the answers

What distinguishes T-cell development from B-cell development in terms of maturation location?

T-cells develop primarily in the thymus Signup and view all the answers

What leads to the formation of a pannus in rheumatoid arthritis?

Thickening and edema of the synovial membrane Signup and view all the answers

Which cell types are primarily involved in the inflammatory infiltrate of the pannus?

CD4+ T cells, B cells, and macrophages Signup and view all the answers

What is a consequence of osteoclastic activity in rheumatoid arthritis?

Bony erosion and osteopenia Signup and view all the answers

Ankylosis in rheumatoid arthritis refers to what?

Formation of a bridge between opposing bones Signup and view all the answers

In what timeframe does the greatest joint damage in rheumatoid arthritis typically occur?

In the first 4-5 years Signup and view all the answers

What is a common characteristic of rheumatoid arthritis (RA)?

Involves inflammation of synovium in typical joints Signup and view all the answers

Which genetic factor is implicated in increasing the severity of rheumatoid arthritis?

HLA DR1 Signup and view all the answers

How does smoking affect the risk of developing rheumatoid arthritis?

Increases the risk between 1.5 – 3.5 times Signup and view all the answers

Which of the following is NOT a common feature of rheumatoid arthritis?

Immediate onset of symptoms Signup and view all the answers

What is the prevalence of rheumatoid arthritis in the worldwide population?

0.5-1% Signup and view all the answers

What is a significant advantage of selective COX-2 inhibitors over non-selective COX inhibitors?

They are less likely to cause gastrointestinal bleeding. Signup and view all the answers

What condition is primarily treated by aspirin due to its unique ability?

Prevention of platelet aggregation Signup and view all the answers

Which long-term risk is associated with selective COX-2 inhibitors?

Higher likelihood of heart attacks and strokes Signup and view all the answers

Which of the following represents a potential severe side effect of COX-inhibitors?

Severe gastrointestinal toxicity Signup and view all the answers

What is a common theory explaining the increased risk of heart attack associated with NSAIDs?

Inhibition of PGI2 formation Signup and view all the answers

What is one of the main organs primarily affected by systemic lupus erythematosus?

Kidney Signup and view all the answers

Which autoimmune antibody is specifically associated with systemic lupus erythematosus?

Anti-ds DNA Signup and view all the answers

What genetic factor is associated with systemic lupus erythematosus due to familial clustering?

HLA DR3 Signup and view all the answers

Which exogenous factor is known to potentially exacerbate systemic lupus erythematosus?

UV light Signup and view all the answers

What is a significant consequence of the inadequate clearance of apoptotic cells in systemic lupus erythematosus?

Continued activation of antigen-presenting cells Signup and view all the answers

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.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

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.