Autoimmunity Mechanisms & Autoimmune Rheumatic Disease Flashcards
(85 cards)
1
Q
what is rheumatic disease?
A
umbrella term referring to arthritis and other conditions that affect the joints, tendons, muscles, ligaments, bones, connective tissues and skin
2
Q
what are examples of non-inflammatory rheumatic diseases?
A
- osteoporosis
- fibromyalgia
- Osteoarthritis
- Charcot joint
3
Q
what are examples of inflammatory rheumatic diseases?
A
- rheumatoid arthritis
- gout/pseudogout
- Systemic lupus erythematosus
- Spondyloarthritis
- Systemic sclerosis (Ssc)
- Sjὅgren syndrome (dry mouth)
- Bullous pemphigoid
- Bechet’s vasculitis
4
Q
what are examples auto-inflammatory diseases?
A
- Bechet’s vasculitis
- Periodic fever syndromes
5
Q
what are examples of inflammatory auto-immune diseases?
A
- Rheumatoid arthritis (RA)
- Systemic lupus erythematosus (SLE)
- Bullous pemphigoid
- Systemic sclerosis (Ssc)
- Sjὅgren syndrome (dry mouth)
6
Q
What part of the immune system causes inflammation in autoinflammatory vs. autoimmune diseases?
A
- Autoinflammatory: Innate immune system (e.g., neutrophils, monocytes)
- Autoimmune: Adaptive immune system (T cells, B cells, autoantibodies)
7
Q
What triggers inflammation in autoinflammatory vs. autoimmune diseases?
A
- Autoinflammatory: Genetic mutations in TRAPS located in TNF1 receptor gene cause spontaneous inflammation without clear triggers
- Autoimmune: Breakdown in immune tolerance leads to self-reactive T/B cells and autoantibodies attacking tissues
8
Q
How does the inflammation pattern differ between autoinflammatory and autoimmune conditions?
A
- Autoinflammatory: Sudden, periodic flare-ups of fever and rash
- Autoimmune: Chronic, progressive inflammation often targeting specific organs
9
Q
What immune components are involved in driving inflammation in each type?
A
- Autoinflammatory: overrelease of IL-1 by inflammasome and TNF by innate immune cells
- Autoimmune: Activation of autoreactive T cells, B cells, and production of autoantibodie
10
Q
what is Behcet’s Disease?
A
Behçet’s disease is an auto-inflammatory systemic vasculitis that presents with mucocutaneous symptoms, especially:
→ Recurrent, large, painful oral and genital ulcers that occur in flare-ups that come and go throughout life
11
Q
What are Periodic Fever Syndromes and how do they present?
A
autoinflammatory diseases involving innate immune overactivation via the inflammasome capsase-1 enzyme that leads to excess release of IL-1β and IL-18, causing inflammation
→ Children present with recurrent fevers, aphthous stomatitis, pharyngitis, and adenitis.
12
Q
What are the common ways to test for inflammatory diseases?
A
- Look for cardinal signs: redness, heat, swelling, pain, and loss of function that are often worse in the morning
- Check acute phase reactants in plasma: ESR (Erythrocyte Sedimentation Rate) and CRP (C-Reactive Protein)
13
Q
What does the ESR test measure and how does it work?
A
- ESR is a blood test that measures how quickly red blood cells settle at the bottom of a test tube in one hour where faster sedimentation = more inflammation.
- It reflects the presence and intensity of inflammation, but it is nonspecific.
14
Q
How is CRP involved in inflammation?
A
CRP is an acute-phase protein that:
- Binds phosphocholine on macrophages
- Detects dead/dying cells or certain bacteria
- Activates complement via C1q
15
Q
What does the CRP test measure?
A
CRP test measures the level of C-reactive protein in the blood, which increases in response to IL-6 from macrophages and T cells
16
Q
What is autoimmunity and how does it occur?
A
breakdown in self-tolerance which leads to:
- Mistaken immune responses against self-antigens
- Targeting of normal tissues, cells, and organs
17
Q
What are the main mechanisms the immune system uses to prevent self-reactivity (maintain self-tolerance)?
A
- Sequestration: Some self-antigens are hidden, so the immune system never “sees” them
- Central Tolerance: T cells and B cells
- Peripheral Tolerance (in the body after lymphocytes mature)
* Checkpoint inhibition to suppress activation
* T regulatory cells to dampen immune responses to self
18
Q
What are immunologically privileged sites?
A
sites that are:
- Physically isolated from immune system surveillance
- Lack lymphatic drainage, so immune cells can’t easily access them
- Protected from immune attack by being invisible to immune cells
** eye, brain, testis, and uterus
19
Q
what does damage to immunologically privileged sites cause?
A
hidden antigens can suddenly be exposed and the immune system may then see these antigens as “foreign” and trigger an immune response, causing autoimmune damage
20
Q
How does central tolerance work in B and T cells?
A
- B Cells: in the bone marrow, self-reactive B cells undergo receptor editing to change their BCRs or undergo clonal deletion (apoptosis) if editing fails
- T Cells: in the thymus, T cells are exposed to self-antigens on MHC I & II, if they bind strongly they are eliminated by negative selection and mTECs use the AIRE protein to present various self-antigens for testing
21
Q
What are 3 ways peripheral tolerance prevents autoimmunity?
A
- Lack of co-stimulation → Anergy (inactive)
- Inhibitory receptors (e.g., PD-1, CTLA-4) turn off T cells
- Tregs suppress autoreactive cells with cytokines and direct contact
22
Q
How do genes contribute to autoimmune diseases and what is an example?
A
Certain autoimmune diseases are linked to specific MHC alleles (like HLA-B27)
- 90% of patients with ankylosing spondylitis have the HLA-B27 gene; however, not everyone with the gene develops disease
23
Q
What environmental factors can trigger autoimmunity?
A
cigarette smoke, gut microbiome imbalance, and infections can initiate disease in people who are genetically susceptible
24
Q
How do sex hormones influence autoimmune disease?
A
Sex hormones (like estrogen) can increase autoimmune risk when combined with genetic and environmental factors
25
What does the hygiene hypothesis say about autoimmunity?
It states that lack of early exposure to microbes (especially in developed countries) leads to an underdeveloped immune system, increasing the risk of autoimmune and allergic diseases
26
What happens when the gut microbiome loses diversity?
The immune system becomes overactive, up-regulators dominate over regulatory cells (like Tregs), and mucosal tolerance decreases, leading to increased autoimmunity
27
What immune mechanisms cause tissue damage in autoimmune diseases?
- Auto-antibodies (e.g., against self proteins or receptors)
- Immune complexes (antigen-antibody clusters that trigger inflammation)
- Cell-mediated immune responses (T cells attacking self tissues)
- Combinations of antibodies and T cell activity
28
What is molecular mimicry and how does it cause autoimmunity?
Molecular mimicry happens when a microbial antigen looks similar to a self-antigen and the immune system attacks the microbe, but then mistakenly attacks body tissues with matching structures
29
How does molecular mimicry cause rheumatic fever?
The immune system makes antibodies against the M protein of Streptococcus because, the M protein shares a similar peptide sequence (e.g., RRDLE) with human heart tissue proteins (myosin).
➤ This leads to cross-reactivity, where the immune system mistakenly attacks the heart.
30
How does molecular mimicry contribute to multiple sclerosis?
EBV proteins have sequences similar to myelin proteins (e.g., VVHFFK... or VYHFVK...)
➤ The immune system targets the virus, but cross-reacts with myelin, leading to nerve damage and symptoms of multiple sclerosis
31
What is bystander activation in autoimmunity?
Inflammatory signals (like cytokines or PAMPs) cause non-specific activation of nearby APCs or autoreactive T/B cells, even if they weren’t specific for the initial trigger
32
What is Epitope Spreading?
two step process where the immune system starts targeting new parts of the same antigen or other nearby antigens after an initial autoimmune response and is a key reason why autoimmune diseases become chronic and more severe over time
33
What are the "first hit" and "second hit" in epitope spreading?
- First hit: Initial break in self-tolerance → production of autoantibodies
- Second hit: Continued immune activation causes attack on additional epitopes → leads to full-blown clinical disease
34
How does the immune system mechanistically spread its response to new epitopes?
- B cells internalize multiple proteins (self-antigens) and present fragments (epitopes) to T helper cells
- T cells recognize foreign or cross-reactive epitopes and activate these B cells that then produce antibodies against new self-epitopes
* This process continues, creating a cascade where more autoreactive B and T cells get involved
35
What is the difference between intramolecular and intermolecular epitope spreading?
- Intramolecular: Autoimmunity expands to target different parts of the same protein (same molecule)
- Intermolecular: Autoimmunity spreads to other proteins in the same tissue or complex (different molecules)
36
what are the two autoantibodies that contribute to Rheumatoid Arthritis?
- ACCP Antibodies (Anti-citrullinated cyclic peptide antibodies)
- Rheumatoid Factor (RF)
37
What is Rheumatoid Factor (RF) and how is it used in RA?
autoantibody that targets the Fc portion of IgG antibodies and is less specific for RA because it appears in other autoimmune and infectious diseases, but its presence is linked to worse prognosis in RA (e.g., bone erosion)
38
How are anti-CCP antibodies produced and how do they contribute to RA?
- immune cells (neutrophils, macrophages) release the enzyme PAD (peptidyl-arginine deiminase) that converts arginine → citrulline in proteins
- During inflammation, neutrophils release NETs (neutrophil extracellular traps), which contain these modified citrullinated proteins (e.g., vimentin, α-enolase, fibrin, type II collagen, filaggrin) that are recognized as foreign
- citrullinated proteins are presented to T cells due to a mutation in MHC molecules
- Anti-CCPs are produced, form immune complexes and contribute to joint damage
39
Which gene is most strongly associated with Rheumatoid Arthritis?
HLA-DRB1 alleles are the strongest genetic risk factor and encode MHC class II molecules that present peptides to T cells and are linked to severe disease
40
What is the role of HLA-DRB1 molecules in RA development?
HLA-DRB1 molecules bind citrullinated peptides (e.g., vimentin, fibrinogen) in their antigen-presenting groove, making them visible to the immune system
41
How does HLA-DRB1 presentation of citrullinated peptides trigger RA?
presentation of citrullinated self-proteins activates antigen-specific T helper cells, which then activate B cells to produce anti-CCP antibodies (ACPAs)
42
What evidence supports HLA-DRB1’s role in RA?
X-ray crystallography shows that HLA-DRB1 molecules can physically bind citrullinated vimentin and fibrinogen, explaining how genetic susceptibility leads to autoimmune activation
43
What environmental factors are associated with increased RA risk and how do they contribute?
- Smoking and pollutant exposure increase citrullinated protein expression in the lungs, promoting autoantibody formation.
- Periodontitis (caused by Porphyromonas gingivalis) introduces a citrullinating enzyme (PPAD) that modifies bacterial and host proteins → can trigger RA autoimmunity.
- Gut microbiome imbalance, especially excess Prevotella copri, is linked to increased citrulline in feces and RA onset.
44
Why is RA more common and severe in women than in men?
estrogen, which affects immune cell activity (e.g., thymocytes, macrophages, endothelial cells) via estrogen receptors, possibly enhancing autoimmune responses
45
What happens when anti-CCP antibodies form immune complexes in RA?
Anti-CCP antibodies bind citrullinated proteins to form immune complexes, that activate the complement system (classical pathway) and activates innate immune cells (monocytes, macrophages, dendritic cells, etc.), leading to inflammation
46
How do dendritic cells and T helper cells contribute to joint inflammation in RA?
Synovial dendritic cells migrate to lymph nodes to activate T cells then activated Th1 and Th17 cells home to inflamed joints, where they promote chronic inflammation
47
What does IL-17 do in the RA synovial tissue?
IL-17, mainly from Th17 cells, promotes release of pro-inflammatory cytokines, chemokines, and MMPs (matrix metalloproteinases), driving tissue damage and inflammation
48
How does IL-17 contribute to pannus formation and bone destruction?
IL-17 stimulates production of VEGF-A, IL-6, IL-8, MMPs in synovial fibroblasts, promoting pannus growth, bone erosion (osteoclastogenesis), and new blood vessel formation (neoangiogenesis)
49
How do joint cells and T-cells contribute to chronic inflammation and tissue damage in RA?
Osteocytes, chondrocytes, and immune cells in the joint cavity initiate inflammation through activated T-cells that stimulate macrophages and fibroblasts, turning them into
- osteoclasts (which break down bone)
- RA-FLS (RA fibroblast-like synoviocytes)
50
What is a pannus and how does it damage joints in rheumatoid arthritis?
- a thickened, inflamed synovial tissue that invades the joint
- causes pain, swelling, and structural damage by pushing into the joint and stretching the joint capsule
51
What role do osteoclasts play in rheumatoid arthritis?
Osteoclasts are activated by RANKL from macrophages and destroy the cartilage matrix and invade bone, contributing to joint erosion
52
What are RA-FLS (Rheumatoid Arthritis – Fibroblast-like Synoviocytes), and how do they contribute to joint destruction?
- synovial lining cells that act like innate immune effectors, expressing TLRs and internalizing NETs that transform in RA , grow anchorage-free and escape contact inhibition, allowing them to behave aggressively
- In vivo, they invade the extracellular matrix, destroy cartilage, and invade bone, driving progressive joint damage.
53
What is the key mechanism that initiates systemic lupus erythematosus (SLE)?
DNase1 fails to clear dying cells, causing their accumulation and triggers the immune system to mistakenly attack the body
54
Which autoantibodies are commonly seen in SLE and what do they target?
- Antinuclear antibodies (ANA) – target nuclear DNA
- Anti-cardiolipin antibodies – target mitochondrial membranes that form immune complexes and deposit in tissues and trigger inflammation
55
What are the major organ systems affected by SLE?
- Joints (arthritis), muscles (myositis)
- Lungs (pleuritis), heart (pericarditis)
- Kidneys (nephritis, proteinuria)
- Brain (seizures, mood disorders), nerves, and circulation
56
What are some hallmark signs of SLE?
- Butterfly (malar) rash over the nose/cheeks
- Oral ulcers (seen in >40% of patients)
- Glomerulonephritis – kidney damage from immune complex deposits
57
How do self-antigens and immune signals promote autoantibody production in SLE?
Self-antigens, along with DAMPs, TLR ligands, and cytokines (BAFF/APRIL), stimulate germinal center formation, leading to the production of autoantibodies by autoreactive B cells
58
What happens after autoantibodies are produced in SLE?
Autoantibodies form immune complexes (ICs) by binding to self-antigens, ICs activate inflammatory pathways where inflammatory cells release cytokines and trigger complement activation
59
How does impaired clearance of dying cells lead to lupus?
Apoptotic debris that isn’t cleared properly, along with reduced phagocytosis, leads to the buildup of nuclear material
60
What is the most distinctive immune feature in systemic lupus erythematosus (SLE) patients?
SLE patients have polyreactive B cells, which produce a wide range of autoantibodies
61
What causes drug-induced lupus (Discoid Lupus) and what medications are commonly involved?
certain medications that stimulate ANA production. Common drugs include:
- Hydralazine (hypertension)
- Quinidine and procainamide (arrhythmias)
- Phenytoin (epilepsy)
- Isoniazid (TB)
- D-penicillamine (RA)
62
What are the clinical signs and prognosis of discoid (skin-limited) lupus?
- Affects only the skin: red, painless, non-itchy rashes with raised borders (usually on the face/scalp)
- May cause permanent hair loss
- Usually resolves after stopping the medication
- 5–10% of cases may progress to systemic lupus
63
What is the hormonal link in systemic lupus erythematosus (SLE)?
SLE symptoms often worsen before menstrual periods due to estrogen influence
64
What is Bullous Pemphigoid and what are the main autoantigens?
- an autoimmune blistering disease that affects skin and oral mucosa where the body mistakenly attacks proteins important for epidermal-dermal adhesion, causing blisters through proteins found in hemidesmosomes:
- BP180: Type XVII collagen (anti-collagen antibody)
- BP230: A plakin protein in the skin’s basement membrane
65
What immune mechanisms contribute to Bullous Pemphigoid?
Imbalance of Th and Treg cells, TLR activation that stimulates B cells, Th17 inflammatory cascade, and complement activation lead to autoantibody secretion and tissue damage
66
What causes blister formation in Bullous Pemphigoid?
Enzyme release breaks down the dermal-epidermal junction, and coagulation activation adds to local inflammation and blistering. Hypercoagulability increases thrombosis risk.
67
What is the primary genetic risk factor associated with Bullous Pemphigoid?
HLA-DQβ1 allele, genetic background of MHC molecules influences how antigens are presented, affecting autoimmune susceptibility
68
What environmental factors can trigger Bullous Pemphigoid?
- UV radiation
- Skin trauma
- Certain medications
69
What is Scleroderma (systemic sclerosis, SSc)?
an autoimmune disease where endothelial cell damage and fibroblast overproduction of extracellular matrix → leads to tissue fibrosis, vascular problems, and organ damage.
70
What are the key autoantibodies in systemic sclerosis?
- Anti-centromere antibodies (ACA) – linked with limited cutaneous disease.
- Anti-Scl-70 (anti-topoisomerase I) – associated with diffuse disease and poor prognosis
71
What oral manifestations are seen in systemic sclerosis?
- Limited jaw opening
- Gum disease (widened periodontal ligament space)
- Tooth loss
- Difficulty eating and drinking
- Mouth changes
72
What are the genetic risk factors for systemic sclerosis?
HLA-DRB1*01 gene is associated with anti-centromere antibodies
73
What are the environmental and hormonal/demographic risk factors for systemic sclerosis?
- Exposure to silica and organic solvents
- Female sex, middle age (45–64 years old)
74
What are the immunological reactions that lead to systemic sclerosis?
- T-helper 2 cells are activated → release IL-4 and IL-13 → stimulate fibrosis
- B cells produce autoantibodies → cause fibroblasts to become pro-fibrotic (excess collagen)
- Macrophages release TGF-β (transforming growth factor beta) and PDGF (platelet-derived growth factor) → promote fibrosis and fibroblast proliferation
75
Which diseases are epitope spreading important in?
SLE, RA, MS, pemphigus, and bullous pemphigoid, and is also involved in Sjogren syndrome, which shares features with SLE
76
What is Sjögren Syndrome and what are the key autoantibodies?
chronic autoimmune disease that attacks secretory glands especially the salivary and lacrimal glands, leading to dry mouth and dry eyes
- Anti-Ro (SS-A) and Anti-La (SS-B) antibodies
77
What is the difference between primary and secondary Sjögren Syndrome?
- Primary SS (pSS): occurs without another autoimmune disease
- Secondary SS: occurs with diseases like SLE, RA, or scleroderma (SSc)
78
What genetic factors, environmental risks and hormonal change are associated with primary Sjögren Syndrome?
- HLA-DR, HLA-DQB1, and HLA-DQA1
- Epstein-Barr virus, air pollutants, smoking, and solvents
- decline in estrogen levels after menopause
79
What is the pathogenesis of primary Sjögren syndrome (pSS)?
- both innate and adaptive immune cells (T cells, B cells, NK cells) infiltrate salivary glands
- Interferons, IL-12, IL-17/23, and BAFF activate autoreactive B cells
- Epithelial cells also drive immune overactivation, not just serve as targets.
80
What is secondary Sjögren syndrome in the context of SLE, and how do autoantibodies progress?
- In SLE, polyreactive B cells produce multiple autoantibodies that appear in a set order (ANA → anti-Ro/La → anti-dsDNA/Sm), often years before symptoms
- Secondary Sjögren syndrome occurs when SLE overlaps with gland inflammation, mainly affecting salivary glands
81
How is a systemic autoimmune disease diagnosed?
Diagnosis is based on pattern recognition using clinical signs and autoantibody testing which are specific and reliable markers that help identify diseases like RA, SLE, or SS, but must be interpreted in context
82
Why must autoantibody titer be ≥1:80?
To reduce false positives—low titers may occur in healthy people
82
What is the significance of anti-CCP and RF in RA testing?
High specificity (88–98%) for RA
- Both positive = strong evidence for RA; both negative = RA unlikely.
83
What autoantibodies are associated with each disease?
- SLE: ANA
- Sjögren syndrome: Anti-Ro (SS-A), Anti-La (SS-B)
- Systemic sclerosis: Anti-Scl-70, Anti-centromere
- RA: Anti-CCP, Rheumatoid factor
84
What are the general treatment goals for autoimmune diseases and what drugs are used?
Control inflammation, slow immune destruction, and preserve function—requires lifelong care
- Corticosteroids (prednisone)
- Methotrexate
- Cyclophosphamide
- Azathioprine
- Cyclosporin
