Autoimmune Disease

19.1.07

Autoimmunity
• Central tolerance.
-Thymus (T-cells).
-Bone marrow (B-cells).
-Clonal deletion of self-reacting cells.
-Come are missed - present in normal health.
• Peripheral tolerance.
-Regulatory CD4+ T-cells [CD=cluster designation - apply to some membrane antigens - ~200, but low numbers tend to be discovered first.]
-Anergy of lymphocytes (irreversible).
-Clonal deletion (activation - induced cell death).
-Antigen hiding.

T-regulator cells
• CD4+, CD25+, foxp3++.
• Suppress autoreactive T-helpers permanently.
• Outcompete other T-cells for APC binding.
• Inactivates antigen-presenting cell (prevents stimulation of other T-cells).
• Binds onto APC adjacent to T-cell and inhibits it directly.

Autoimmunity
• Loss of tolerance.
-Genetic factors (HLA, AIRE, Fas, CTLA-4).
-Infection.
§General factors.
~Cytokines.
~Release of damaged proteins.
~Molecular mimicry.
§Homologous sequences e.g. strep.
-Hidden sites: special effects in eye, brain, testes.
• Generalised.
-Connective tissue disorders.
• Single/restricted organ damage.
-Hashimoto's.
-Pernicious anaemia.
-Goodpasture's.
-etc.

Connective tissue disorders
• Rheumatoid arthritis.
• Systemic lupus erythematosus (SLE).
• Scleroderma.
• Etc.

Rheumatoid arthritis
Overview
• Systemic disease, mainly involving joints, but also:
-Blood vessels.
-Skin.
-Muscles.
-Lungs.
-Heart.
• Incidence ~1%, mainly F 40-70 (F:M ratio = 3:1).

Joints
• Stages.
-Villous synovitis.
-Vascularises.
-Fibrinous exudates (rice bodies and pmn).
-Osteoclastic activity increased.
§Erosions, cysts, juxta-articular osteoporosis.
-Pannus formation.
§Synovium and granulation tissue.
§Covers and erodes cartilage.
§Bridging and anklosis.

Other sites
• Skin.
-Rheumatoid nodules (elbow, head, back).
§Necrosis and palisaded macrophages.
• Blood vessels.
-Vasculitis.
§Neuropathy and gangrene.

Pathogenesis
• Immunology: excessive CD4+ cells, but unknown trigger (??Proteus).
• Twin concordance - genetic, but not simples.
• No clear HLA linkage.
• Immune complex deposition.
• Excessive TNF and IL-1 from macrophages and synovial cells.

Clinical
• Onset.
-Often slow, with:
§Malaise.
§Fatigue.
§Generalised pain in limbs.
-Small joints involved first.
§Hands and feet, tends to progress centrally.
• Hot, swollen joints.
-Develop deformities later.
• Painful after resting.
• Remitting, relapsing disease.
-Baker's cyst.
• X-ray findings.
-Erosions, narrowed joint, osteoporosis.
• Tests - none very specific/sensitive.
-Rheumatoid factor.
§IgM anti IgG-Fc.
-ESR.
• Diagnosis in presence of more than three of the following:
-Morning stiffness.
-More than two arthritic joint groups.
-Hands involved.
-Symmetrical involvement.
-X-ray changes.
-Rheumatoid nodules.
-Rheumatoid factor.

SLE
• Most protean (multisystem) of them all.
• Chronic remitting relapsing disease, often febrile, characterised by injury to skin, joints, kidney, serosal membranes.
• Incidence: 1/2500, F:M ratio = 9:1, age 10-30 commonest (1:700 young women).

Clinical
• May start acutely.
-Sudden onset.
-High fever.
• Red raised (malar) rash frequently present.
• Frequent, recurrent pleurisy.

Genetics
• Twins (20% vs 2%).
• HLA (A1, A8, DR-2, DR-3).
• Inherited complement deficiency (C1q, C2, C4 in 6%).
• C1q needed to clear apoptotic cells.

Environmental
• Drugs.
-Penicillamine.
-Procainamide.
-Hydrallazine.
• UV light.
-?immunosuppressive role.

Hormonal
• Sex hormones.
-Much commoner in females.
-SLE may flare during:
§Pregnancy.
§Menstruation.

Serology
• Antinuclear antibodies:
-D-DNA.
-S-DNA.
-RNA.
-RNA protein.
-Histone.
-Nucleoli.
• Anti-blood cell antibodies: immune complexes.
• Patients affected in %:
-Fever 84%.
-Skin rash 72%.
-Renal 60%.
-Pleural 50%.
-Heart 50%.
-CNS 25%.
• Remitting fever with crises etc.
• Criteria:
-Renal damage.
-CNS signs (seizures, psychosis etc.)
-Blood cytopenias.
-Autoantibodies (including antiphospholipid).

Anti-phospholipid antibodies
• Actually directed against plasma proteins complexed to somewhere else.
• May give false and WR (cardiolipin).
• Lupus anticoagulant in vitro, but…
• Procoagulant in vivo.
-DVT.
-Repeated miscarriage.
-Cerebral ischaemia.

Scleroderma
• Main characteristic: excessive fibrosis throughout body.
• Skin, GIT, kidney, heart, muscle, lungs.
• F:M ratio = 2-5:1.
• Immunology: activated CD4+ cells in skin of many patients.
• Characteristic antibodies: Scl 70, anti-centromere.
• Hypotheses:
1. Autoimmune trigger for collagen synthesis.
2. Abnormal collagen metabolism.
3. Microvascular abnormality.
• Clinical.
-Thickening of hand ± Raynaud's.
-Articular pain.
-Dysphagia.
-Pain.
-Obstruction.
-Malabsorption.
-Renal damage.
-Hypertension.
-Diffuse fibrosis.
• "CREST": benign variant: calcinosis, Raynaud's, oesophageal fibrosis, sclerodactyly.

Polymyositis/dermatomyositis
• Myopathy and weakness due to degenration of groups of muscle fibre, with inflammation.
• Types.
-Typical adult myositis, dermatomyositis.
-Malignant associated (12%).
-Childhood.
-Associated with other connective tissue disease.
• Immunology:
-Some antinuclear antibody, possibly specific.
-Childhood type features immune complexes.
• Clinical.
-Initially arm, then proximal leg.
-Later, extends to limb girdles, neck, pharynx, intercostals and diaphragm.
-Initial oedema, then atrophy.

Sjögren's disease
• Primary: sicca syndrome.
• Secondary: with other autoimmune diseases.
• Decrease in salivary and lachrymal secretions due to lymphocytic infiltrate and fibrosis.
• Immunology:
-Some B-cells.
-75% have RF.
-65% have antinuclear factor.
-LE test positive in 25%.
-Antibody to duct cells, smooth muscle mitochondria, GPC, thyroid.
-SS-A and SS-B antibodies.
-If RA also present, RANA found.
• Clinical.
-Corneal ulceration.
-Oral fissuring and ulceration.
-Dry nose.
-Possible bronchial involvement.
-25% cases involve extraglandular tissues.