Paraneoplastic neurological antibodies

Basic information on antibodies associated with paraneoplastic neurological syndromes is given in this section. Antibodies listed below are non pathogenic and well characterised. In the absence of a detectable tumour, their detection in patients leads to a definitive diagnosis of paraneoplastic neurological syndrome. (Click to select)

Hu (ANNA1) antibodies

Hu antibody
 Cerebellum Rodent stomach
Hu antibody binds to the granular and Purkinje neurones. Rodent stomach Anti-Hu antibody staining myenteric plexus.
Hu blot
This is the most commonly occurring paraneoplastic neurological antibody.

Neurological syndrome: Cerebellar ataxia, encephalomyelitis, sensory neuropathy

Associated tumour: Small cell lung carcinoma and neuroblastoma


Yo (PCA-1) antibodies

Yo antibody
Yo antibody (also known as Purkinje cell antibody type 1 (PCA-1)) reacts with primate cerebellum with coarse granular staining of the Purkinje cell cytoplasm. This reaction must be confirmed with Western blot/line blot.

Note: the red neuronal nuclei are due to ethidium bromide counterstain.
Yo blot
Western blot: Yo (IgG type) antibody recognised both the recombinant and 62 kDa band. In some cases a second 34 kDa band is also seen.

Clinical indication: Cerebellar degeneration

Associated tumours: Breast and ovarian carcinomas. With only few exceptions PCA are found exclusively in female patients.


CV2/CRMP5 antibodies

CV2 antibody

CV2/CRMP5 is a 66 kDa protein found in the cytoplasm of oligodendrocytes in the white matter.
CV2 antibody
When this antibody was first described, it was called CV2 and now it also known by its antigenic protein (collapsing response mediator protein 5; i.e CRMP5)

Clinical conditions: Paraneoplastic encephalomyelitis/sensory neuropathy

Associated tumours: Thymoma, small cell lung carcinoma.


Ri (ANNA2) antibodies

Ri antibody
Rare antibodies (IgG)

Similar staining pattern as anti-Hu antibody

Antibody binds to CNS but not PNS neurones (myenteric neurones stain negative)

A high intensity signal at both 55 and 80 kDa on a Western blot would confirm Ri specificity.

Neurological syndrome: Cerebellar degeneration, opsoclonus/myclonus

Associated tumours: Breast, gynaecological and small cell lung carcinoma


Amphiphysin antibodies

Amphiphysin
Amphiphysin (128 kDa dimeric, synaptic protein) is found in cerebellar presynaptic nerve terminals. The cell processes in the molecular layer are stained more intensely than the nerve terminals in the granular layer. The pattern in the granular layer resembles that of GAD.
Amphiphysin
Amphiphysin can also coexist with Hu, CV2 or PCA-2.

Clinical conditions: Stiff person’s syndrome (5%), paraneoplastic encephalomyelitis.

Associated tumours: Most common malignancies are small cell lung carcinoma and breast cancer


Ma antibodies

Three types are known, Ma1 (Ta), Ma2 and Ma3. These have a similar pattern of distribution on the cerebellum. All three antibodies can coexist with each other and this is reflected by additional symptoms compared to isolated reactivity.

Cerebellum: Ma is located in nucleoli of the molecular and Purkinje neurones. Nucleolar ANA must be eliminated as it produces similar pattern as Ma. This type of distribution can also be seen with non Ma sera of undetermined significance

Testis: Nucleoli are target antigens for the anti-Ma antibody. Positive testis indicates Ma1 reactivity. Note testis lack Ma2 reactivity. This implies that the above sample contains both Ma1 and Ma2 reactivity.

Positive for Ma2 (recombinant antigen coated on nitrocellulose).

Tumour: Ma1: Various tumours. Ma2 usually found in younger males with testicular tumour.

Syndrome: Ma1: Brainstem/cerebellar syndrome. Ma2; Brainstem, cerebellar, limbic signs.

Tr antibodies

There are several antibodies (for example, Yo, PCA-2 and Tr) which have different specificities yet react with Purkinje cell cytoplasm thus producing a similar immunofluorescence distribution pattern. For this reason it can be difficult to differentiate between them by immunofluorescence alone. Alternative methods (such as Western blot) must be employed to confirm specificity of the antibody. 

Primate cerebellum: Anti-Tr IgG stains the cytoplasm of Purkinje cells together with the dendrites. In the molecular layer, punctate (dotted) pattern further distinguishes from Yo. The staining in the Purkinje cells is finer than that of anti-Yo antibodies. The identification of Tr is based on immunocytochemical distribution alone, as no common band has been identified by Western blot analysis.

Associated tumour: Hodgkin's disease

Neurological syndrome: Cerebellar degeneration

Departmental publications

A R Karim and S Jacob (2012)
Immunological markers in neurological disorders
Ann. Clin. Biochem. 49:29-43

Abid R Karim and S Jacob (2010), "NEUROIMMUNOLOGY" in "Immunology" ISBN-13: 9780199534968, Hall and Yates, Oxford University Press, pp174-209
Karim A R (2010), Cancer, neurological disorder and autoimmunity: Coexisting antibodies. The Biomedical Scientist, 54(3):189-193

Bradwell A R, Hughes R G, Hunt MJ, Karim AR (2008). Atlas of autoantibody patterns, 3rd edition, Printers KNP Group Ltd, Redditch, UK, ISBN

Karim A R (2008), Antibodies in paraneoplasia. Modern Medicare, 4(6):42-44

Abid R Karim, Richard G Hughes, Mohammed El lahawi and Arthur R Bradwell (2007), “PARANEOPLASTIC NEUROLOGICAL ANTIBODIES: NUCLEAR” In "Textbook of Autoantibodies" second edition, ISBN: 978-0-444-52763-9, Shoenfeld, Gershwin and Meroni, Elsevier Press, pp627-635.

Abid R Karim, Richard G Hughes, Mohammed El lahawi and Arthur R Bradwell (2007), “PARANEOPLASTIC NEUROLOGICAL ANTIBODIES: PURKINJE CELL CYTOPLASM” "Textbook of Autoantibodies" second edition, ISBN: 978-0-444-52763-9, Shoenfeld, Gershwin and Meroni, Elsevier Press, pp637-643.

Abid R Karim, Richard G Hughes, Mohammed El lahawi and Arthur R Bradwell (2007), “PARANEOPLASTIC NEUROLOGICAL ANTIBODIES: ADDITIONAL REACTIVITIES” "Textbook of Autoantibodies" second edition, ISBN: 978-0-444-52763-9, Shoenfeld, Gershwin and Meroni, Elsevier Press, pp645-652.

Bradwell A. R, Hughes R C & Karim A R (2006). “Immunofluorescent Antinuclear Antibody Tests” in Manual of Molecular and Clinical Laboratory Immunology, 7th Edition, ISBN-10: 1-55581-364-X, Barbara Detrick, Robert G Hamilton and James D Folds, ASM Press, pp995 – 1006.

Karim AR (2006). An introduction to paraneoplastic neurological antibodies. The Biomedical Scientist, 50(11):966-969

Karim AR, Hughes RG, Winer JB, Williams AC, Bradwell AR. Paraneoplastic neurological antibodies: a laboratory experience. Ann N Y Acad Sci. 2005 Jun;1050:274-85.