3.5 about 30 minDeep Learning viewL3 p.33–43

Autoimmune disease

Self-reactive lymphocytes are made every day. Autoimmune disease follows when the checks that delete, silence or suppress them fail in a genetically susceptible person and something in the environment sets them off. The injury then uses the same hypersensitivity mechanisms as any other immune attack.

Tolerance and how it fails

L3 p.34

Because receptors are made at random (3.1), the body continually produces lymphocytes that recognize self. Tolerance is the set of checks that keeps them harmless. Central tolerance acts while lymphocytes are developing; peripheral tolerance catches those that escape.

Teaching schematic

Central tolerance (developing lymphocytes)

  • Thymus: negative selection with AIREAIRE mutation → APS-1
  • Thymus: some self-reactive cells become Tregs
  • Marrow: B-cell receptor editing or deletionSelf-reactive B cells survive (estrogen)

Peripheral tolerance (mature lymphocytes)

  • Anergy: antigen without B7–CD28; CTLA-4, PD-1Checkpoint-blocking drugs → colitis, thyroiditis
  • Tregs (FOXP3, CD25): IL-10, TGF-βFOXP3 mutation → IPEX; CD25 variants → MS, T1DM
  • Deletion through Fas–FasLFas mutation → ALPS

Susceptibility × trigger. HLA (B27, DR4, DR3), sex hormones, complement defects; then infection (molecular mimicry, costimulation), tissue injury releasing hidden antigens, UV light.

Central tolerance in the thymus and marrow; peripheral tolerance in tissues and lymph nodes. Each check has a disease that appears when it fails.L3 p.34

The checks, and what happens when each failsL3 p.34

  • Negative selection with AIRE

    Where
    Thymic medulla (central)
    How it works
    Tissue antigens are displayed; strongly self-reactive thymocytes die or become Tregs
    If it fails
    APS-1 (autoimmune polyendocrine syndrome): hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis

  • Receptor editing, deletion

    Where
    Bone marrow (central, B cells)
    How it works
    A self-reactive immature B cell rearranges a new light chain or dies
    If it fails
    Self-reactive B cells survive (estrogen may reduce their deletion, one reason SLE favors women)

  • Anergy

    Where
    Periphery
    How it works
    Antigen seen without costimulation (no B7–CD28), or with inhibitory CTLA-4 and PD-1, switches the T cell off
    If it fails
    Checkpoint-inhibitor cancer drugs cause autoimmune colitis, thyroiditis, hepatitis

  • Suppression by Tregs (FOXP3, CD25)

    Where
    Periphery
    How it works
    Tregs consume IL-2 and secrete IL-10 and TGF-β
    If it fails
    IPEX (FOXP3 mutation, X-linked): neonatal diabetes, enteropathy, eczema in boys; CD25 polymorphisms → MS, type 1 diabetes

  • Deletion (apoptosis)

    Where
    Periphery
    How it works
    Repeatedly stimulated T cells die through Fas–Fas ligand
    If it fails
    Autoimmune lymphoproliferative syndrome (Fas defect): lymphadenopathy, autoimmune cytopenias

Susceptibility genes set the stage. HLA alleles shape which self-peptides are presented: HLA-B27 (class I) with ankylosing spondylitis, psoriatic arthritis, IBD-associated and reactive arthritis; HLA-DR4 (class II) with rheumatoid arthritis; DR2 and DR3 with SLE. Triggers then break tolerance: infections that look like self (molecular mimicry, as streptococcal M protein and cardiac myosin in rheumatic fever) or that switch on costimulators in tissues; tissue injury that releases hidden antigens (sympathetic ophthalmia, 3.1); ultraviolet light, which makes skin cells die and expose nuclear antigens in SLE; and female sex hormones.

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

A girl inherits two nonfunctional copies of AIRE. Complete the chain to her autoimmune disease.

One gap needs the mechanism in the thymus; another the event that follows in the tissues.

  1. Medullary thymic epithelial cells lack AIRE
  4. in the periphery they meet their antigens with costimulation
  6. organ failure appears through childhood
  7. APS-1: chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency

Cards

Tap or drag a card. Placing a used card moves it.

Systemic lupus erythematosus: mechanism and manifestations

L3 p.36–38

SLE is a chronic multisystem autoimmune disease of women of childbearing age (20–45 years; about 9 women per man). Its central defect is a failure to tolerate nuclear antigens. Several things combine:

  • Too much nuclear antigen in view. Dying cells (after UV exposure, for instance) are cleared poorly, and their DNA and nucleosomes linger. Inherited deficiency of the early complement components C1q, C2 and C4, which normally help clear apoptotic debris and immune complexes, raises the risk strongly.
  • Loss of tolerance. HLA-DR2/DR3 and other genes allow self-reactive B and T cells to be activated; nucleic acids in immune complexes stimulate TLRs inside B cells and plasmacytoid dendritic cells, which produce type I interferon and keep the response going.
  • Antibodies to many nuclear and cell-surface antigens. DNA–anti-DNA complexes deposit in glomeruli, skin, joints, serosa and small vessels and fix complement (type III). Antibodies against red cells, platelets and leukocytes cause cytopenias (type II). Antiphospholipid antibodies cause thrombosis.
L3 p.36

Manifestations and the mechanism behind eachL3 p.37

  • General

    Findings
    Fever, fatigue, weight loss
    Mechanism
    Cytokines, interferon

  • Skin and mucosa

    Findings
    Malar (butterfly) rash sparing the nasolabial folds; discoid lesions in sun-exposed skin; photosensitivity; oral ulcers; alopecia
    Mechanism
    Immune complexes at the dermal–epidermal junction; UV-induced keratinocyte death

  • Joints

    Findings
    Arthralgia/arthritis of ≥2 joints, often PIP and MCP, symmetric, nonerosive and nondeforming
    Mechanism
    Immune complexes in synovium

  • Blood

    Findings
    Autoimmune hemolytic anemia (Coombs positive), thrombocytopenia, leukopenia, lymphopenia; lymphadenopathy, splenomegaly
    Mechanism
    Type II antibodies

  • Kidney

    Findings
    Nephritic or nephrotic syndrome (below); chronic renal failure is a common cause of death
    Mechanism
    Immune complexes in glomeruli

  • Heart and lungs

    Findings
    Fibrinous pericarditis, pleuritis, Libman–Sacks (sterile verrucous) endocarditis, myocarditis, interstitial fibrosis, Raynaud phenomenon
    Mechanism
    Immune complexes, vasculitis

  • Nervous system

    Findings
    Headache, psychosis, seizures, chorea, strokes
    Mechanism
    Vasculitis, antibodies, antiphospholipid thrombosis

  • Pregnancy

    Findings
    Recurrent miscarriage; congenital heart block in the baby
    Mechanism
    Antiphospholipid antibodies; maternal IgG anti-Ro/La crossing the placenta and damaging the fetal conduction system

  • Bone

    Findings
    Avascular necrosis of the femoral head, osteoporosis
    Mechanism
    Corticosteroid treatment, vasculitis

Lecture image

Three images: a red malar rash over the cheeks and nose sparing the nasolabial folds; an opened heart with small warty vegetations on both surfaces of a valve; and round red scaly discoid plaques on an arm.
From the lecture's SLE collage: malar rash sparing the nasolabial folds; Libman–Sacks endocarditis, small sterile vegetations on both surfaces of the valve leaflets; and discoid plaques in sun-exposed skin.L3 p.38

Lupus nephritis: nephritic or nephrotic?

Diffuse proliferative (class IV)

  • Most common and most severe form
  • Complexes in the subendothelial space and mesangium, close to the blood, so neutrophils and complement reach them
  • Proliferation, thick 'wire-loop' capillaries
  • Nephritic: hematuria, red-cell casts, proteinuria, hypertension, falling GFR

Membranous (class V)

  • Complexes in the subepithelial space, outside the basement membrane, away from inflammatory cells
  • Little proliferation; the podocyte barrier is damaged
  • Nephrotic: massive proteinuria, hypoalbuminemia, edema, hyperlipidemia
  • Little hematuria
L3 p.37

Autoantibodies and laboratory tests

L3 p.35, 39

Every autoantibody test trades sensitivity (how often it is positive in the disease, good for ruling out) against specificity (how rarely it is positive in anything else, good for ruling in). The screening test for SLE is sensitive but not specific; the confirmatory antibodies are specific but miss many patients.

Antibodies to knowL3 p.35, 39

  • ANA (immunofluorescence)

    What it means
    Antibodies to any nuclear antigen; positive in ~98% of SLE but also in drug-induced lupus, systemic sclerosis, Sjögren syndrome, infections and healthy older people
    Use
    Screening: a negative ANA makes SLE very unlikely

  • Anti-dsDNA

    What it means
    Highly specific for SLE; levels rise with active nephritis
    Use
    Confirm SLE; follow renal activity

  • Anti-Smith (anti-Sm)

    What it means
    The most specific SLE antibody, but present in only about a quarter of patients
    Use
    Confirm SLE

  • Anti-Ro (SS-A), anti-La (SS-B)

    What it means
    Cross the placenta → neonatal lupus and congenital heart block; also Sjögren syndrome, subacute cutaneous lupus
    Use
    Screen lupus pregnancies

  • Antihistone

    What it means
    In over 90% of drug-induced lupus (hydralazine, procainamide, isoniazid)
    Use
    Drug-induced lupus spares the kidney and brain and fades when the drug stops

  • Antiphospholipid

    What it means
    Lupus anticoagulant (prolonged PTT), anticardiolipin (false-positive VDRL/RPR), anti-β₂-glycoprotein I
    Use
    Explain clots and pregnancy loss (next topic)

  • Complement C3, C4

    What it means
    Low in active disease because immune complexes consume them
    Use
    Follow activity

  • ESR and CRP

    What it means
    ESR raised in active SLE; CRP often normal unless serositis or infection
    Use
    A high CRP in a lupus flare suggests infection

  • Anti-U1 RNP

    What it means
    High titer is the marker of mixed connective tissue disease; also found in SLE
    Use
    —

  • Organ-specific

    What it means
    Anti–parietal cell (proton pump) and anti–intrinsic factor antibodies in pernicious anemia
    Use
    —

Lecture image

Six fluorescent nuclei labelled speckled, homogenous, mixed, nucleolar, centromere and peripheral.
ANA immunofluorescence patterns. Homogeneous and peripheral (rim): antibodies to dsDNA and histones (SLE, drug-induced lupus). Speckled: extractable nuclear antigens (Sm, RNP, Ro, La). Nucleolar: systemic sclerosis. Centromere: discrete dots, one per chromosome, in limited systemic sclerosis (CREST).L3 p.35

Antiphospholipid syndrome: the clotting paradox

L3 p.37, 39

Antiphospholipid antibodies are aimed at proteins that bind phospholipid, chiefly β₂-glycoprotein I and prothrombin. They occur in about a third of SLE patients (secondary syndrome) or alone (primary). The syndrome is diagnosed when the antibodies persist and the patient has thrombosis (venous: deep-vein thrombosis, pulmonary embolism; or arterial: stroke in a young person) or pregnancy morbidity (recurrent miscarriage, fetal loss, placental insufficiency).

Teaching schematic

In the test tube

  1. Antiphospholipid antibodies bind the phospholipid in the clotting reagent
  2. Factor complexes cannot assemble on it
  3. PTT prolonged; mixing with normal plasma does not correct it
  4. Anticardiolipin reacts with VDRL/RPR antigen → false-positive syphilis screen

Looks like a bleeding tendency: hence the misleading name 'lupus anticoagulant'.

In the patient

  1. Antibodies bind β₂-glycoprotein I on endothelium, platelets, monocytes, trophoblast
  2. Cells activated; tissue factor expressed; complement activated
  3. Natural anticoagulants (protein C) impaired
  4. Venous and arterial thrombosis; placental thrombosis → pregnancy loss

Treat with anticoagulation. Continues in Chapter 4 (thrombosis).

In the test tube the antibodies tie up the phospholipid that clotting factors need, so the PTT is prolonged. In the body they activate endothelium, platelets, monocytes and complement, so the patient clots.
  • The paradox. The lupus anticoagulant prolongs phospholipid-dependent clotting tests such as the PTT, and mixing with normal plasma does not correct it (an inhibitor, not a factor deficiency). Yet the patient is prothrombotic: in vivo the antibodies activate endothelial cells and platelets, induce tissue factor on monocytes, activate complement and interfere with natural anticoagulants. The name is a laboratory artifact.
  • False-positive syphilis test. The VDRL and RPR detect antibodies against cardiolipin, a phospholipid. Anticardiolipin antibodies react with the test antigen, so the screening test is positive while specific treponemal tests are negative. A young woman with a 'positive VDRL', no sexual history and oral ulcers should make you think of SLE (Case III Q10).
  • Pregnancy loss comes from thrombosis and complement-driven inflammation in the placenta.
  • Treatment is anticoagulation (heparin with aspirin in pregnancy). The thrombotic side of the story continues in Chapter 4: thrombosis and embolism.
L3 p.37, 39

Systemic sclerosis: from damaged vessels to fibrosis

L3 p.40–43

Systemic sclerosis (scleroderma) is excess deposition of normal collagen in skin and organs on a background of small-vessel damage. Women are affected about four times as often as men, usually between 35 and 64. The sequence explains the clinical picture:

Vascular injury to fibrosis

  1. Autoantibodies and T cells injure endothelium (digital vessels first)
  2. NO and prostacyclin fall; vessels constrict → Raynaud phenomenon
  3. Damaged endothelium releases PDGF and TGF-β
  4. CD4 Th2 cells add IL-13 and TGF-β
  5. Fibroblasts lay down collagen; perivascular fibrosis narrows lumens
  6. Ischemia and fibrosis of skin, gut, lungs, kidneys
L3 p.40

Diffuse and limited (CREST) forms

Diffuse cutaneous

  • Skin thickening spreads proximally to the arms and trunk, rapidly
  • Early visceral disease: interstitial lung fibrosis, renal crisis, heart
  • Anti-Scl-70 (DNA topoisomerase I): highly specific
  • Worse prognosis

Limited cutaneous (CREST)

  • Skin of fingers, hands, forearms and face; Raynaud for years first
  • Calcinosis cutis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia
  • Anticentromere antibody
  • Late pulmonary arterial hypertension
L3 p.40–41, 43

Lecture image

Six images: a taut expressionless face with a small mouth; tapered fingers with tight shiny skin; a fingertip with ulcers and calcinosis; enlarged nailfold capillary loops; facial telangiectasias; and a chest x-ray with bilateral lower-zone interstitial shadows.
Systemic sclerosis in the lecture: A mask-like 'stone' facies with a small mouth; B sclerodactyly; C digital ulceration with calcinosis; E dilated, distorted nailfold capillaries; facial telangiectasias; and interstitial lung fibrosis.L3 p.42

Organ by organL3 p.41

  • Skin

    What happens
    Swollen fingers, then firm thickened skin extending proximally; taut face without wrinkles, small mouth; telangiectasias; abnormal nailfold capillaries
    Clinical result
    Sclerodactyly, digital ulcers, 'stone facies'

  • Esophagus

    What happens
    Smooth muscle of the lower two-thirds atrophies and is replaced by collagen; the lower esophageal sphincter becomes incompetent
    Clinical result
    Dysphagia, reflux, strictures, Barrett esophagus

  • Stomach and intestine

    What happens
    Dysmotility, villous atrophy, wide-mouthed diverticula
    Clinical result
    Postprandial bloating, malabsorption, constipation

  • Lungs

    What happens
    Interstitial fibrosis; pulmonary arterial hypertension
    Clinical result
    Restrictive disease, dyspnea, dry cough; leading cause of death

  • Kidneys

    What happens
    Intimal thickening of interlobular arteries ('onion-skin'), fibrinoid necrosis of arterioles, thrombosis
    Clinical result
    Scleroderma renal crisis: malignant hypertension, acute kidney failure (treated with ACE inhibitors)

Lecture image

Small renal artery whose lumen is almost obliterated by concentric layers of loose pale intimal tissue, giving an onion-skin appearance.
Kidney in systemic sclerosis: a small artery with concentric, onion-skin intimal thickening that nearly closes the lumen. Downstream ischemia drives renin release and malignant hypertension.L3 p.41

Knowledge check · 3.5

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 7 correct
  1. Q1SLE: anti-dsDNAL3 p.35, 37, 39Ch. III cases p.7

    A 21-year-old woman has had malaise, joint pain, weight loss and intermittent fever for 3 months. Temperature is 38 °C. She has a malar rash, erythematous plaques with telangiectatic vessels, oral ulcers and nonblanching purpuric papules on her legs. Blood urea nitrogen and creatinine are raised.

    Antibodies to which antigen would be expected in her serum?

  2. Q2SLE: anti-Smith; false-positive VDRLL3 p.35, 39Ch. III cases p.11

    A 17-year-old girl has a painful, swollen left elbow and fever; days earlier her right knee was swollen. She has several oral ulcers. ANA is weakly positive, she is anemic, and a VDRL test is positive although she has never been sexually active.

    Which antibody is most specific for her condition?

  3. Q3Systemic sclerosis: anti-Scl-70L3 p.40–43Ch. III cases p.5

    A 42-year-old woman has severe headaches and difficulty swallowing. Over 6 months she has noticed small red lesions around her mouth and thickening of her skin. She has a taut, expressionless 'stone' facies.

    Which antigen is the most specific target of autoantibody in this disease?

  4. Q4Scleroderma esophagusL3 p.41Ch. III cases p.10

    A 45-year-old woman with scleroderma diagnosed 5 years ago has increasing difficulty swallowing.

    Which abnormality of esophageal muscle most likely causes her symptoms?

  5. Q5Antiphospholipid paradoxL3 p.37, 39Ref.

    A 31-year-old woman has had two miscarriages and now a deep-vein thrombosis. Her PTT is prolonged and does not correct when her plasma is mixed with normal plasma. A screening VDRL is positive, but a treponemal test is negative.

    Which explanation fits all of these findings?

  6. Q6Image: centromere ANA patternL3 p.35, 40–43

    A 58-year-old woman has had Raynaud phenomenon for 12 years and now has tight skin on her fingers, small calcified nodules on her fingertips and telangiectasias on her face. Her ANA shows many discrete, evenly sized dots scattered across each nucleus.

    Lecture image

    Six fluorescent nuclei labelled speckled, homogenous, mixed, nucleolar, centromere and peripheral.

    Which panel matches her ANA, and which antibody does it indicate?

  7. Q7Tolerance: FOXP3 and IPEXL3 p.34

    A 3-month-old boy has insulin-requiring diabetes, chronic watery diarrhea with failure to thrive, and widespread eczema. His maternal uncle died in infancy with similar problems.

    Which gene is most likely mutated, and which tolerance mechanism has failed?

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