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ANTIBODIES & COMPLEMENT IN MYOPATHIES AND NMJ DISORDERS

General topics

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


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
  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 antibodies11
    • 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 HistidylRNA 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 Antisynthetase syndrome 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-RNAcomplex
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
Nailfold lesions
Nucleoplasm
Fine speckled
PMS1 6 PMS1 DNA mismatch
  repair enzyme
Immune myopathy (7%)
DM/PM/Fasciitis
 
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
CADM-140 MDA5 (IFIH1) Immunity vs viral infection
Detection of viral dsDNA
Dermatomyositis, Amyopathic
ILD: Rapid progression
Skin: Ulcers; Palmar papules
Cytoplasmic
MJ (p140)
MU 15
NXP-2
  140 kD protein
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  

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-nRNP 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
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
Speckled


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

Cytoplasmic antigens Nuclear antigens Nucleolar 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
  Classical pathway
  Alternative pathway
Functions
Muscle diseases & complement
Serine proteases

Complement activation: Two pathways Complement system functions Complement in muscle disease


Myopathies: Antibody Testing Laboratories


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References

1. Sem Arth Rheum 1995;24:323-358
2. Current Opinion in Neurology 1996;9:226-234
3. Current Opinion in Rheumatol 2000;12:369-373
4. Current Opinion in Rheumatol 2000;12:374-378
5. Ann Neurol 1995;37:41-46, Neurology 1997;49:1650-1654
6. Arth Rheum 2001;44:389-396
7. Arth Rheum 2002;46:1595-1613
8. Current Rheumatology Reports 2002;4:434–441, Curr Opin Rheumatol. 2007;19:523-529, Curr Opin Rheumatol 2008;20:675-680, Medicine (Baltimore) 2013;92:223-243
9. Arthritis Res 2001;3:102–106, Arthritis Rheum 2004;50:565-569, J Rheumatol 2011 Aug 15, Clin Exp Rheumatol. 2012 Jan 16
10. Neurology 2004;62:1891–1893
11. J Rheumatol 2007 Feb 15
12. Arthritis Rheum 2007;56:1295-1303
13. J Rheumatol 2007 Oct 15
14. Arthritis Rheum 2006;54:3682-3689, Arthritis Rheum 2011 Sep 27, Arthritis Rheum 2011 Oct 10, Arthritis Rheum 2011 Oct 10
15. Arthritis Rheum 2005;52:1571-1576, Arth Rheum 2009;60:1807–1814
16. Arthritis & Rheumatism 2009;60:1112–1118
17. Arthritis & Rheumatism 2009;60:3784–3793
18. Autoimmun Rev 2010 Sep 18
19. J Am Acad Dermatol 2011;65:25-34, Rheumatol Int 2011; On-Line Dec 25, J Am Acad Dermatol 2011;65:25-34,
      Rheumatology 2011 Dec 30, Arthritis Care Res 2013; Online Feb 22
20. J Immunol Methods 2012 Aug 2
21. European Journal of Internal Medicine 2013; Online Feb, Autoimmunity Reviews 2012;11:739–745
22. Respiratory Medicine 2011;105:1238-1247
23. Medicine (Baltimore) 2012;91:95-102

6/18/2014