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Step 1: Genetic Predisposition
- The HLA-B27 gene (a specific gene linked to immune function) is present in 90–95% of people with AS.
- HLA-B27 is a class I MHC molecule (a protein on cell surfaces that helps the immune system recognize threats) involved in antigen presentation to T-cells (showing invaders to immune cells that attack).
- Not everyone with HLA-B27 develops AS, suggesting a multifactorial cause (caused by a mix of genes, environment, and immunity).
Step 2: Triggering Factors (Environmental & Microbial)
- Gut dysbiosis (imbalance of bacteria in the digestive tract), especially Klebsiella pneumoniae (a common gut bacterium), is implicated.
- Mucosal infections (infections in moist linings like the gut or mouth) or mechanical stress (wear and tear) at entheses (spots where tendons/ligaments attach to bones) may trigger inflammation.
- The “gut-joint axis” theory (the idea that gut health affects joint health) suggests microbial antigens (foreign proteins from gut bacteria) may cross-react (mistakenly get attacked) with spinal tissues via molecular mimicry (the immune system confuses body tissue with invaders).
Step 3: Immune Activation
- The innate immune system (first line of immune defense) is activated first:
- Dendritic cells and macrophages (immune cells that detect and attack invaders) recognize microbial antigens or tissue damage.
- IL-23 (a signaling protein that boosts immune response) is released, activating Th17 cells (a type of helper immune cell).
- Adaptive immune system (targeted immune response):
- Th17 cells produce IL-17 (another protein that causes inflammation), a key player in AS.
- CD8+ T-cells (killer immune cells) may also be involved, especially in HLA-B27-positive individuals (people with the gene).
Step 4: Inflammation of Entheses (Enthesitis)
- The hallmark (main) lesion of AS is enthesitis (inflammation where tendons/ligaments attach to bone).
- Common sites: sacroiliac joints (lower back joints), vertebral bodies (spine bones), Achilles tendon, costosternal junction (where ribs meet breastbone).
- Inflammatory cytokines (chemical messengers that trigger inflammation) involved:
- TNF-α (tumor necrosis factor alpha)
- IL-17, IL-23
- IL-6, IFN-γ (interleukin-6 and interferon gamma)
Step 5: Structural Damage & Bone Erosion
- Chronic inflammation leads to:
- Erosion of subchondral bone (wearing away of bone beneath the cartilage)
- Cartilage degradation (breakdown of cushioning in joints)
- Fibrosis at entheses (scarring where tendons/ligaments attach to bones)
- MRI findings: bone marrow edema (swelling inside the bone), erosions (wear), and fatty changes (fat replacing damaged tissue)
Step 6: Pathologic New Bone Formation
- Unlike many other types of arthritis, AS causes new bone growth:
- Happens through endochondral ossification (process where cartilage slowly turns into bone).
- Leads to syndesmophytes (bony bridges between spine bones).
- Result: Spinal fusion (ankylosis) (bones in the spine join together) and reduced mobility (stiffness and limited movement), especially in late stages.
Step 7: Axial & Extraspinal Manifestations
- Axial: affects the spine and sacroiliac joints (core skeleton)
- Peripheral: involves joints in hips, knees, shoulders
- Extra-articular (outside the joints):
- Uveitis (eye inflammation causing redness, pain, blurred vision — up to 40% of AS patients)
- Inflammatory bowel disease (chronic gut inflammation)
- Cardiac involvement (heart issues like valve problems or irregular heartbeat)
- Pulmonary fibrosis (scarring of lung tissue, mainly in upper lobes)
🧠 Summary Flow (Layman-Friendly):
Genetic Risk (like HLA-B27)
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Trigger from Gut Bacteria or Injury
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Immune System Overreacts
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Inflammation Where Ligaments Attach to Bone
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Damage to Bone and Cartilage
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Extra Bone Grows → Spine Fuses Together
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Symptoms: Stiff Back, Eye Problems, Gut Issues, Fatigue
