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Myopathies & NMJ Disorders: Antibodies & Complement

General topics

Antibodies
  ANCA
  Cytoplasmic
  DNA
  Myositis-Overlap
  Myositis-Specific
  Nuclear
  Nucleolar
  Ribonucleoproteins
  Striational
  tRNA synthetases
  Types
Complement
Connective tissue disorders
Lambert-Eaton myasthenia
M-protein
  Amyloid: Light chain
  Anti-Decorin myopathy: IgM
  Scleromyxedema: IgG
Myasthenia gravis
Neuropathy
Scleroderma
Specific antibodies

56 kD RNP
Acetylcholine receptor
CADM-140
Centromere
Double-stranded DNA
FHL-1
Fibrillarin
Fibroblast
Giantin
Histones
Jo-1
Ku
MGT-30
Mi-2
Nucleosome
p140
p155 (TIF1γ)
Phospholipid
PM-Scl
Rheumatoid factors
RNP
  Nuclear
    U1-nRNP
    U2-nRNP
    U3-RNP
  Ribosomal
Signal Recognition Particle
Sm
SS-56
SSA (Ro)
SSB (La)
tRNA Synthetase


Normal IgG

Myasthenia Gravis
Lambert-Eaton Myasthenic Syndrome
Anti-Decorin (BJ antigen) Myopathy 5

ANTIBODIES IN CONNECTIVE TISSUE DISORDERS 1

Antibody types
  Cytoplasmic
  Nuclear
  Nucleolar
  Phospholipid
Myositis-associated
  tRNA synthetase
  Juvenile
  Other
Myositis overlap

MYOSITIS-ASSOCIATED ANTIBODIES: General 8
  • Specificity
    • High for inflammatory myopathies
    • Muscle pathology types: IMPP & Other
  • Sensitivity: 1% to 35%
  • Antibody class: IgG
  • MSA target antigen features
    • Not tissue specific
    • Usually enzyme protein, not tRNA
      • Exception is anti-PL-12 with tRNAAla & enzyme targets
    • Often expressed in regenerating muscle fibers
    • Cleaved by granzyme B
  • Anti-Aminoacyl t-RNA synthetase antibodies 11
    • Associated clinical features
      • Interstitial lung disease: Most common
      • Myositis
      • Fever
    • Myositis syndrome: May be myositis ± skin changes
    • Lower frequency of associated neoplasm when present
    • Treatment of syndrome: Commonly requires steroid + another agent
    • May be stimulated by apoptotic bodies in skin

MYOSITIS-ASSOCIATED ANTIBODIES
Aminoacyl t-RNA synthetase Antibodies: IMPP syndromes
Autoantibody tRNA-Synthetase Antigen Antigen function Clinical associations HEp-2 IIF pattern
Jo-1 Histidyl Protein synthesis
  Intracytoplasmic

Amino acid binding
  to cognate tRNA
PM 15%-30%; DM-like 13%
Lung fibrosis (ILD)
Skin rash: Mechanics hands
Raynauds
Arthritis
Fever
Specificity > 95%
HLA: DRw52; DRB1*0301
Cytoplasm: Speckled
PL-7 Threonyl PM/DM 3%-5% of cases
Antibody +: ILD > 90%
    Milder than Jo-1
Cytoplasm: Speckled
PL-12 Alanyl PM/DM 3%
Antibody +: ILD > 90%
Skin lesions
Cytoplasm
Speckled (dense)
EJ Glycyl Antibody +: ILD > 90%;
    DM 10% to 80%
Cytoplasm
OJ Isoleucyl PM/DM <3%
Antibody +: ILD > 90%
Skin lesions
Cytoplasm
KS Asparaginyl 12 Antibody +: ILD > 90%
    Myositis: 25%
Skin lesions
Japanese
Cytoplasm
Zo Phenylalanyl Myopathy + ILD Cytoplasm
Ha (YRS) Tyrosyl Antisynthetase syndrome Cytoplasm
Other Antibodies
Autoantibody Antigen Antigen function Clinical associations HEp-2 IIF pattern
SRP Signal recognition particle
  54 kD protein
  In 7SL-RNA complex
Protein translocation
  Intracytoplasmic
  (Endoplasmic reticulum)
Immune polymyopathy
  Specificity 93%
  Acute onset; Severe
HLA DRw52
Cytoplasm: Speckled
Nucleolus
Mi-2 Helicase protein part of
  NuRD complex
Nuclear transcription DM 5% -35%; PM 5%-9%
HLA DRw53
Rash: V- & Shawl-sign
Cuticular overgrowth
Nucleoplasm
Fine speckled
PMS1 6 PMS1 DNA mismatch
  repair enzyme
Immune myopathy (7%)
DM/PM/Fasciitis
 
TIF1γ/TIF1α
p155/p140
14
Transcriptional intermediary
  factors (TIF; TRIM33):
  p155 = 1γ ; p140 = 1α
Nuclear transcription
Cellular differentiation
Dermatomyositis (20%)
  JDM (32%)
Skin ulceration & edema
Cancer-associated DM (75%)
Nucleus
MDA5 IFIH1 (CADM-140) Immunity vs viral infection
Detection of viral dsDNA
Dermatomyositis, Amyopathic
ILD: Rapid progression
Skin: Ulcers; Palmar papules
Cytoplasmic
NXP-2 15 Morc3
Nuclear transcription Dermatomyositis,
  Juvenile (23%); Calcinosis
Adults: Lung Δ; Neoplasm
Cytoplasm
SAE Small-ubiquitin-like
  modifier enzyme (SUMO)
Post-translational modification
  Nuclear transcription factors
Dermatomyositis, Adult (< 5%)
  Amyopathic early
 
Decorin Chondroitin sulfate Extracellular matrix Immune myopathy Basal lamina
Ku Thyroid autoantigen, 70-kD
  G22P1
DNA protein kinase
  regulatory subunit
Systemic sclerosis
PM/Scleroderma
Japanese
Nucleolus & Nucleus
Homogeneous
KJ   ? Translation factor PM < 1%; Raynaud's
Lung Fibrosis
Cytoplasm
Speckled (dense)
HMGCR
  (200/100)
3-Hydroxy-3-Methylglutaryl
  -Coenzyme A Reductase
Cholesterol biosynthesis Myopathy + Myalgias
? Statin use
 
Mup44 NT5C1A   IM-VAMP; sIBM
Systemic sclerosis; SLE
 
Cortactin
CTTN   Immune myopathies  
Nuclear pore
Nuclear pore proteins   Myopathy + Systemic ANA: Peripheral
FHL1
FHL1   PM > DM > IBM  

MYOSITIS-OVERLAP ANTIBODIES
  • Associated with PM and other connective tissue disorders
  • Sensitivity for connective tissue disorders up to 95%
  • Antibody class: IgG
Autoantibody Antigen Clinical associations HEp-2 IIF pattern
PM-Scl Exosome: RNA
processing complex
PM/Scl-100
PM/Scl-75
PM 8%-12%
Scleroderma 25%
Caucasian
Nucleolus & Nucleus
Homogeneous
56 kD RNP component PM/DM 87%
Other CTD 10%
High with active disease
?
SSA/Ro 2 proteins
  & 4 small RNAs
PM/DM 5%-10%
Sjögren's 90%
Nucleoplasm
Fine speckled
U1-snRNP 3 proteins:
  22, 33 & 70 kD
PM/DM 4%-17%
SLE & Scleroderma 30%
MCTD 95%
Nucleoplasm
Speckled
U2-nRNP Small nuclear RNP PM/DM 4%-17%
SLE & Scleroderma 30%
Nucleoplasm
Speckled
U3-nRNP
Fer Elongation factor 1a PM/DM (rare)
?
MAS tRNA bindingSer
  protein
PM/DM (rare)
HLA DRw53
Rhabdomyolysis
Myalgias
Diffuse cytoplasm
Mitochondrial PDC-E2 Histiocytic IM
1° Biliary cirrhosis
Disease severity
Speckled
HSF1 HSF1 IIM + Neoplasm: 17%
Other: RA, Sjögren 12%

Immune myopathies, Juvenile (JIIM): Antibody associations 28



CONNECTIVE TISSUE DISEASE: ANTIBODY TYPES (ANA is IIF pattern on HEp-2 cells)

Cytoplasmic antigens Nuclear antigens Nucleolar Antigens
DNA Ribonucleoproteins Anti-Phospholipid Antibodies 4 Antifibroblast antibodies (AFAs) Rheumatoid factors (RF)
CREST = Calcinosis; Raynaud's; Esophageal dysmotility; Sclerodactyly; Telangectasias

COMPLEMENT IN HUMAN MUSCLE DISEASE 2

Activation pathways
  Classical
  Alternative
  Lectin
Functions
Muscle diseases & Complement
Serine proteases
Complement Pathways 40

C4bC2b (Classical or Lectin Path) or C3bBb (Alternative Path)
 ↓  C3 convertase
C3C3aC3aR (Tau; Aβ; Age; Ca++ barrier)
 ↓
C3biC3bCR3
 ↓
Binds to C4bC2b or C3bBb
 ↓  C5 convertase
C5C5a
 ↓
C5b
 ↓ |--Clusterin; CD59
Membrane Attack Complex (MAC; C5b-9)

Complement activation: Three pathways
  • Proteins in Complement cascade
  • Complement activation Pathways
    • Classical
      • Triggered by: Antigen-Antibody complexes
      • C1 binds complexes & is activated
      • C4b2a
        • Formation: Catalyzed by activated C1
        • Action: Activates C3 via C3 convertase
      • C3b: Produced from C3 ; binds C4b2a
      • C5b: Produced from C5 ; Catalyzed by C4b2a3b
      • Membrane attack complex (MAC) formation
        • Formed by binding of C6 , C7 , C8 & C9 to C5b
    • Alternative
      • Triggered by: Pathogens; Injured self; C3(H20)
      • Spontaneously available C3b binds Factor B
      • C3bBb
        • Formed by cleavage catalyzed by Factor D
        • Action: Activates C3 via C3 convertase
      • C3b: Produced from C3; Catalyzed by & binds C3bBb
      • C5b: Produced from C5; Catalyzed by C3Bb3b; + Properdin
      • MAC formation
        • From binding of C6, C7, C8 & C9 to C5b
    • Lectin
      • Stimulus: Lectin binds mannose on pathogens
      • Mediators: MASPs; C4; C2
      • C4b2a
        • Formation: Catalyzed by activated C1
        • Action: Activates C3 via C3 convertase
      • Effect on: C3 Convertase
      • Terminal pathway: MAC formation
Complement system functions Complement in Neuromuscular disorders Systemic Disorders: Complement deficiency

Myopathies: Antibody Testing Laboratories


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