Nerve: Autoantibodies

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NEUROPATHY, CNS SYNDROMES & SERUM AUTOANTIBODIES

General: Testing Antibody Targets Glycolipids Glycoproteins Index Intracellular antigens Oligosaccharides Receptors Vasculitis
	IgG	IgA	IgM

General Antibodies: Testing

Monoclonal antibodies (M-proteins): Serum or urine
- Use immunofixation methodology as the initial test.
Cryoglobulins
- Serum should be kept warm before testing
- When cryoglobulins are detected, test for
  - Monoclonal antibodies
  - Hepatitis C
  - Collagen Vascular Screen

Clinical Syndromes Associated with Autoantibodies

Antibodies vs Glycolipids & Glycoproteins

Anti-GM1 antibodies: Motor syndromes
- IgM vs GM1
  - Motor: Asymmetric, Distal, Chronic
  - Demyelinating or Axonal
- IgG vs GM1
  - Signs: Motor predominant; Occasional sensory loss also
  - Syndromes
    - Acute: Symmetric, with Campylobacter jejuni infection, or
    - Chronic: Asymmetic, Distal, without conduction block.
Polyneuropathy with anti-MAG antibodies
- Sensory > Motor, Symmetric, Distal > Proximal
- May also have gait ataxia or tremor
- Demyelination with prolonged distal latencies
  - But only rarely conduction block.
Polyneuropathy with anti-Sulfatide antibodies
- Signs: Sensory loss
- Syndromes
  - M-protein (IgM): GALOP syndrome; Weakness; Demyelinating
  - Polyclonal (IgM or IgG): Dysesthesias; Axonal
Anti-GQ1b antibodies (IgG)
- Miller Fisher Syndrome
- Antibodies associated with ophthalmoplegia or ataxia
Antibodies vs. GALOP (Central Myelin Lipid) Antigen (CMA)
- GALOP Syndrome (Gait disorder; Autoantibody; Late-age-Onset; Polyneuropathy)
Anti-GD1b antibodies
- IgM: Ataxic sensory neuropathy
- IgG: Acute sensory ± motor neuropathy
Anti-GD1a antibodies
- IgM: Demyelinating motor neuropathies (in the setting of an IgM M-protein) & lower motor neuron syndromes.
  - Most serums with this IgM reactivity also show binding to GM1 ganglioside
- IgG: Motor, & axonal Guillain-Barré-like syndromes (AMAN) & motor neuropathies.
Anti-GalNAc-GD1a antibodies
- Campylobacter jejuni infection
- Acute motor neuropathies
- Distal predominant weakness & Sparing of the cranial nerves
- Rapidly progressive, severe weakness

Antibodies vs Intracellular antigens

Anti-Hu (ANNA-1) antibodies (IgG in serum & CSF)
- Associated with Small Cell Neoplasms, especially lung
- Clinical syndromes are combinations of:
  - Sensory neuronopathy
  - Limbic encephalitis
  - Cerebellar disorders
  - Autonomic & Gastrointestinal
Anti-Yo antibodies (IgG in serum & CSF)
- Associated with gynecologic neoplasms.
- Clinical syndrome is cerebellar ataxia.
Anti-Tubulin antibodies (IgM > IgG)
- CIDP (asymmetric)
IgM vs Neurofilaments
- Polyclonal: Opsoclonus-Myoclonus syndromes
- Monoclonal: Axonal sensory neuropathy
IgG vs Amphiphysin (128kDa) ¹
- Protein: Vesicle membrane
- Neoplasm association: Breast cancer
- Clinical associations
  - Stiffman syndromes: Breast cancer associated
  - Encephalomyelitis with rigidity
  - Neuropathy (60%)
    - Polyneuropathy
    - Autonomic neuropathy: Gastroparesis
    - Sensory neuronopathy
  - Other paraneoplastic disorders
    - Cerebellar syndrome
    - Opsoclonus-myoclonus
Immune Myopathies
Stiffman syndromes
- Glutamic acid decarboxylase
- Pancreatic islet cell (60%)
  - Also found in type I diabetes: Lower titer, different staining pattern
- Amphiphysin (128kDa)
- 80 kDa protein
Vasculitis: Anti-neutrophil cytoplasmic antibodies (ANCA)
- c-ANCA
- p-ANCA

Antibodies vs Receptors & Channels

IgG vs P/Q-type Voltage Gated Calcium Channel (Conotoxin w-MVIIC binding; CACNB2)
- Myasthenic syndrome (Lambert-Eaton)
AChR, subunit α3
- Autonomic neuropathy
- Small cell lung cancer
Also see
- Other AChRs
  - Myasthenia gravis: Anti-AChR antibodies
  - AChR disorders
  - NMJ & muscle autoantibodies
  - Paraneoplastic syndromes
- Ion Channels

Other Autoantibodies

Vasculitis & Autoantibodies

Anti-Neutrophil Cytoplasmic Antibody (ANCA): General ²
- Epidemiology: More frequent with silica dust exposure
- Methodology
  - Initial testing by immunocytochemistry
  - Confirmation by Western blot: Binding to specific antigen
  - Antibody type
    - Diagnostic purposes: IgG
    - Other described: IgA; IgM
- ANCA effects
  - Bind to: Neutrophils & Endothelial cells; Azurophilic granules
  - Promote degranulation of neutrophils & monocytes: Facilitates endothelial damage
  - Endothelial activation: Neutrophil adherence is enhanced
  - Release of cytotoxic superoxide and serine proteases
- Clinical associations
  - Neuropathy
    - Onset: Paresthesias
      - May be painful
      - Often single nerve territory
    - Anatomic pattern
      - Mononeuritis multiplex
      - Legs > Arms
    - Modalities: Motor + Sensory
    - Cranial nerves: Uncommon, except for GPA
    - Partial multisystem disorders
      - Common: Arthralgia & Arthritis, Myalgia, Fever, Weight loss, Cutaneous, Mucous membrane & ENT
      - Less common: Life-threatening organ involvement; Pulmonary, Renal, Cardiovascular, Abdominal
  - Muscle involvement ⁴⁸
    - Myalgias
    - Serum CK: Usually normal
    - Muscle MRI: T2 signal increased in multiple extremities
  - Rare
    - Polyarteritis nodosa with no inflammation in vessels smaller than arteries
    - Nerve-specific inflammatory vasculopathy (vasculitis)
  - Prognostic
    - Continued or recurrent ANCA positivity after treatment: Increased likelihood of relapse
  - Treatments of ANCA-associated vasculitis
    - Active diseaase
      - Corticosteroids
      - Cyclophosphamide: Pulse; Intravenous
      - Methotrexate
      - Rituximab
      - Anti-interleukin-5 therapy (Mepolizumab)
    - Maintain remission
      - Corticosteroid, Low dose + Other immunomodulating agent
- Clinical syndromes: Subgroups
  - Granulomatosis + Polyangiitis (GPA; Wegener's)
    - Clinical
      - Necrotizing glomerulonephritis
      - Respiratory tract: Granulomatous inflammation
    - Antibody (80%): PR3-ANCA (cANCA)
    - Neuropathy association: 17%
  - Eosinophilic Granulomatosis + Polyangiitis (EGPA; Churg Strauss)
    - Clinical: Asthma
    - Blood: Eosinophilia
    - Antibody (35%): MPO-ANCA (pANCA) or Negative
    - Neuropathy
      - Association: 77%
      - Pathology
    - ANCA negative EGPA
      - More: Cardiac
      - Less: ENT; Neuropathy; Renal
  - Microscopic polyangiitis (MPA)
    - Pathology: No granulomas
    - Antibody (80%): MPO-ANCA or PR3-ANCA
    - Neuropathy association: 23% to 58%
  - Organ limited
  - Vasculitic Neuropathy: Systemic Associations
    - More: MPO-ANCA+; Skin; Musculoskeletal; Cardiovascular
    - Less: Renal, Ocular, Gastrointestinal
- Laboratory
  - Associated antibody: LAMP-2
    - Present with Pauci-immune necrotizing crescentic glomerulonephritis (NCGN)
  - CSF: Normal protein & cells
  - NCV: Axon loss, Sensory & Motor
  - Serum NfL: High
  - Pathology
    - Vasculitis
      - Patterns
      - Lesion Locations
        
        Epineurium
        
        Axon loss more prominent: Distal to middle of nerve trunk
      - Neutrophils
        
        Attached to: Vascular endothelial cells
        
        Bind to: ANCA
    - Axon loss: Myelinated & Unmyelinated
ANCA antigens
- c-ANCA (PR3-ANCA)
  - Antigen: Proteinase-3 (PR3; PRTN3)
  - Geography
    - More common: Northwest Europe & North-America
  - Disease specificity
    - Granulomatosis + Polyangiitis (GPA; Wegener's)
    - Renal involvement (Necrotizing glomerulonephritis): Common
    - vs MPO-ANCA
      - Younger onset (57 vs 63 yrs)
      - More involvement: ENT & Eye; Respiratory; Extra-renal
  - Disease association: Vitamin D levels low
  - Pathology: Granulomatous inflammation
  - Pathogenicity
    - Leukocyte activation: Potentiated by TNF-α
    - Increased ICAM-1 expression on endothelial cells → Leukocyte adhesion
- p-ANCA (MPO-ANCA)
  - Antigen: Myeloperoxidase (MPO)
  - Geography
    - More common: South Europe & East Asia
  - Clinical: Initial upper limb symptoms more common (44%)
  - Laboratory: Serum C-reactive protein levels higher
  - Nerve pathology
    - Vasculitis: Inflammatory vasculopathy more common
    - Eosinophils: Less prominent
  - Disease associations ³
    - Eosinophilic Granulomatosis + Polyangiitis (EGPA; Churg Strauss): Associations with pathology
      - Vessels: Necrotizing vasculitis; Fibrinoid necrosis
      - Epineurium: No eosinophils
      - MPO-ANCA: 30% to 40%
    - Microscopic polyangiitis (MPA)
    - Pauci-immune Glomerulonephritis: Kidney limited disease
    - Alveolar hemorrhage
    - Drug associations: Propylthiouracil, Hydralazine, D-penicillamine, Minocycline
    - vs PR3-ANCA (c-ANCA)
      - Fewer: Relapses
      - More: Cardiovascular risk; Renal severity
- Atypical perinuclear ANCA (pANCA)
  - Antigens: Elastase; Lactoferrin, BPI, Cathepsin G
  - Disease associations: Ulcerative colitis; Vasculitis, drug-induced; Systemic lupus erythematosus (SLE)
- Other ANCA antigens
  - Disease associations: Vasculitis; Inflammatory bowel; Hepatitis; Rheumatoid arthritis; Lupus
- Human neutrophil elastase (HNE)
  - Vasculitis during treatment with propylthiouracil
  - Cocaine-induced midline destructive disease

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References
1. J Neurol Neurosurg Psychiatry 2004;75:658-662
2. Kidney Int 2010 Dec 8, Nat Rev Rheumatol 2010;6:653-664, Anti-Neutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis 2020, Neurol Ther 2022 Jan 19
3. Neurology 2020;94:e1726-e1737

12/2/2024