ANTIBODIES & COMPLEMENT IN MYOPATHIES AND NMJ DISORDERS

Myasthenia Gravis

• Anti-Acetylcholine Receptor (IgG)
• Anti-Striational (IgG): With Thymoma

Lambert-Eaton Myasthenic Syndrome

• Anti-P-type Calcium Channel (IgG)

Anti-BJ Myopathy M

• Clinical features
• Weakness: Proximal; Symmetric; Slowly progressive
• Serum CK: High
• Serum IgM vs BJ antigen: Often with
• IgM M-protein
• Waldenström's macroglobulinemia
• BJ antigen is
• Glycoprotein
• Located in muscle basal lamina
• EMG: Myopathic ± spontaneous activity
• Muscle pathology
• Variable muscle fiber size
• Endomysial fibrosis
• Endomysial deposition of IgM
• Serum IgM binding to muscle endomysium

ANTIBODIES IN CONNECTIVE TISSUE DISORDERS¹

ANTIBODY TYPES (ANA is IIF pattern on HEp-2 cells)

Cytoplasmic

• anti-tRNA synthetases (IgG)

• Antigen: Jo-1 = histidyl tRNA synthetase : 50-52 kD
• Interstitial Lung Disease
• Raynaud's
• Arthritis
• Onset: Spring
• ANA: Cytoplasmic (speckled)
• Immunology

• Therapy

• Other: Associated with similar clinical syndrome & cytoplasmic ANA

• PL-12 = alanyl :
• PL-7 = threonyl
• EJ = glycyl
• OJ = isoleucyl
• Lysyl

• anti-KJ
• ANA: Cytoplasm (dense speckled)
• Antigen: Unidentified factor in protein translation
• Clinical: Similar to anti-synthetase antibodies

• anti-Signal Recognition Particle
• ANA: Cytoplasm (speckled) and nucleolus
• Antigen: 54 kD protein
• In particle with 6 proteins and 7SL-RNA
• HLA DRw52
• Clinical
• Onset: Acute; Fall
• Severe myositis
• No overlap with other connective tissue diseases
• Resistant to Treatment

• Ribosomal RNP
• Antigens: Phosphoproteins in elongation step of protein synthesis
• ANA: Cytoplasmic (dense); Nucleolar (homogeneous)
• Clinical
• SLE

• 56 kD RNP component
• ANA: ?
• Clinical
• Polymyositis/Dermatomyositis: 87%
• Other connective tissue diseases: 10%
• Titers related to disease activity

Nuclear

• Centromere
• ANA: Diffuse speckled nuclear
• HLA type: Non-leucine residue at position 26 of HLA-DQB1 chain
• Clinical
• CREST (60% to 80%)
• Raynaud's: Primary

• dsDNA (Double-stranded DNA)
• ANA: Homogeneous nuclear pattern
• Clinical
• Active SLE (40% to 70%)
• Nephropathy: High avidity antibody
• CNS: Low avidity antibody

• anti-Mi-2
• ANA: Speckled nuclear pattern
• HLA type
• DRw53; DR7 in most
• Tryptophan at position 9 of DRß chain
• Clinical
• Dermatomyositis without other associated connective tissue disorders

• anti-Ro/SSA
• 52 kD , 60 kD & ? 48 kD antigens
• ANA: Fine speckled nuclear
• Clinical
• Sjögren's syndrome (> 95%)
• Lupus (35% to 50%):

• anti-La/SSB
• ANA: Fine speckled nuclear
• Leucine at position 26 of HLA-DQB1 chain
• Clinical
• Lupus; Especially neonatal
• Sjögren's syndrome

• Histones
• ANA: Homogeneous nuclear pattern
• Clinical
• Drug induced SLE (95%)
• Systemic sclerosis with lung fibrosis

• Sm
• Core proteins of U-snRNPs
• ANA: Coarse speckled nuclear pattern
• Clinical
• SLE

• anti-U1-nRNP : 70 kDa polypeptide
• ANA: Coarse speckled nuclear pattern
• Mixed connective tissue disease
• Swollen hands & fingers
• Synovitis
• Myositis or myalgia
• Raynaud's
• ± Acrosclerosis
• Associated disorder: Rheumatoid arthritis

• anti-U2-nRNP
• ANA: Speckled ribonuclear pattern
• Scleroderma

Nucleolar

• anti-PM-Scl (IgG)
• Nucleolar protein complex
• ANA: Homogeneous nucleolar & nuclear
• Polymyositis + Scleroderma
• Skin: Dermatomyositis-like; Machinist's hands
• Raynaud's phenomenon
• Calcinosis
• Telangectasia

• Fibrillarin (U3-RNP)
• ANA: Clumpy nucleolar
• Antigen: 34 kD protein in U3-RNP particle
• Clinical
• CREST
• Systemic sclerosis: Skeletal muscle; Small bowel; Pulmonary hypertension

• anti-Ku (IgG)
• ANA: Homogeneous nuclear & nucleolar
• Antigens: 60-70 & 80-86 kD proteins
• Polymyositis + Scleroderma in Japan

DNA

• Double stranded (dsDNA)
• Native: SLE > > other connective tissue disease
• Single stranded
• 70% in active SLE
• Many connective tissue disorders
• ANA: Negative

Ribonucleoproteins

• U1RNP
• U2RNP
• Sm: SLE
• SSA (Ro) & SSB (La)
• anti-56kD

CREST = Calcinosis; Raynaud's; Esophageal dysmotility; Sclerodactyly; Telangectasias

COMPLEMENT IN HUMAN MUSCLE DISEASE²

Complement activation: Two pathways

• Classical pathway
• Triggered by antigen-antibody complexes
• C1 binds complexes & is activated
• C4b2a formation is catalyzed by activated C1
• C3b: Produced from C3 ; binds C4b2a
• C5b: Produced from C5 ; Catalyzed by C4b2a3b
• Membrane attack complex (MAC):
• Formed by the binding of C6 , C7 , C8 & C9 to C5b

• Alternative pathway
• Spontaneously available C3b binds Factor B
• C3bBb: Formed by cleavage catalyzed by Factor D
• C3b: Produced from C3; Catalyzed by & binds C3bBb
• C5b: Produced from C5; Catalyzed by C3Bb3b; With properdin
• MAC: Formed from the binding of C6, C7, C8 & C9 to C5b

Complement system functions

• Membrane attack complex (MAC): Complex of C5b-9
• Induces cytolysis
• Main mechanism playing a role in muscle diseases
• Biologic effects of proteolytic fragments of complement
• Phagocytosis: Opsonization & promotion
• Inflammation mediated by anaphylotoxins (fragments of C3, C4 & C5): Activation
• Immune complexes: Solubilization & phagocytic clearance
• Leukocyte recruitment: C3a, C4a, C5a
• Phagocytosis enhancement:
• C3b, C4b, iC3b, vitronectin interact with complement receptors

Complement in muscle disease

• Necrosis of muscle fibers in myopathies
• MAC binding: Intracellular organelles
• Complement activation:
• ? alternative pathway
• Possibly facilitated by Ca⁺⁺-active neutral proteases
• Effects
• Removal of necrotic debris
• Allows myofiber regeneration
• Damage to post synaptic membranes in myasthenia gravis
• MAC binding: Post-synaptic membrane
• Associated with IgG binding
• Effects
• Simplification of post-synaptic membrane folding
• Reduction in # of AChRs
• Widening of synaptic cleft
• Dermatomyositis: Especially childhood
• MAC binding: Intramuscular capillaries, venules ± arterioles
• IV Ig treatment: Reduces MAC binding
• Effect: Perifascicular myopathy
• Necrotizing myopathy with pipestem capillaries
• MAC binding: Capillaries
• Effect: Necrotic myofibers
• X-linked vacuolated myopathy
• MAC binding
• Sarcolemma & internal vacuoles; Granular appearance
• Vessels
• Effect: Shedding of sarcolemma into internal vesicles

Myositis-specific antibodies and lupus screen are evaluated at:

Oklahoma Medical Research Foundation
Clinical Immunology Laboratory
825 N.E. 13th Street, C-323
Oklahoma City OK 73104
Phone: (405) 271-7771

BJ antibodies are evaluated at:

Neuromuscular Clinical Laboratory
Washington University, St. Louis

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6/24/97

References

1. Sem Arth Rheum 1995;24:323-358
2. Current Opinion in Neurology 1996;9:226-234