Known Cross-Reactions: Campylobactor jejuni,3 Streptococcal proteins,4 gliadin6

Antibodies Appear:

• Chronic Inflammatory Demyelinating Polyneuropathy 2
• Cerebrovascular Accidents 1
• Cranial Trauma 1
• Guillain Barré Syndrome 3
• Miller Fisher Syndrome 3
• Motor Neuron Disease1, 2 MMNBC1
• Multifocal Motor Neuropathy 2
• Multiple Sclerosis 1
• Myasthenia Gravis 1
• PANDAS / ANDAS / OCD5
• Rheumatoid Arthritis 1
• Sensorimotor Neuropathy 2
• Systemic Lupus
• Erythematosus 1, 2

GM1 is exposed at the surface of spinal motor neurons, and in the peripheral nerves, it is limited to the node and paranodal region.

Low levels of antibodies can be found in normal individuals and in patients with certain autoimmune disorders, however, high titers may be helpful in the diagnosis of multifocal motor neuropathy with conduction block (MMNCB),2 and paraproteinenia including motor neuron disease and multifocal motor neuropathy.1

Autoantibodies to ganglioside GM1 are thought to be involved in the pathophysiology of some motor neuropathies due to relatively high level detection prior to therapeutic intervention, and a subsequent decrease of antibodies concurrent with clinical improvement.1

High titers of IgM Antiganglioside GM1 may be etiologically important in certain types of motor neuropathy, while on the other hand, low levels of antibodies may represent B-cell dysfunctional regulation.2

The origin of anti-ganglioside antibodies is unknown, however, it is speculated that they can be formed against certain infectious microorganisms.

Campylobacter jejuni has been identified as a frequent cause of Guillain Barré syndrome and Miller Fisher syndrome; during infectionof C. jejuni anti-GM1 antibodies bind with whole cells of different C. jejuni isolates.4 Likewise, this occurs with Streptococcal infection, which is a trigger for PANDAS, the adult version, ANDAS and OCD.4, 5

ALPHA + BETA TUBULIN

Tubulin is a building block protein and a major component of a cell’s internal cytoskeleton, called microtubules.

These structures play key roles in many cellular functions including, interaction with guanine, lateral contacts, interaction with beta and gamma phosphates of nucleotides, interaction with gamma phosphate, longitudinal contacts, backbone interactions with a and b phosphates, hydrophobic contact of conserved residues, nucleotide contacts, MAP-binding domain and acetylation site.

Known Cross-Reactions: Streptococcal Protein 7

Antibodies Appear:

• Alcoholic liver disease1
• Demyelinating disease1
• Graves’ disease1, 5
• Hashimoto’s thyroiditis1, 5
• Infectious agent exposure1,
• 7PANDAS/ANDAS/OCD7
• Rheumatoid arthritis1
• Recent onset diabetes type
• 16 Toxin exposure7

Clinical Significance:

Tubulin’s basic function as a component of microtubules explains its appearance in a variety of unrelated disorders, which can affect organ tissues, as well as, neuronal structures.3, 4

Quantitative increases in anti- tubulin antibodies are thought to be due to autoimmune reactions to the patient’s own tubulin, or to the polyclonal activation of B cells associated with diseases and disorders listed above.1

A surprising similarity between the structures of tubulin and bacterial protein FtsZ (filamenting temperature-sensitive mutant Z) has spawned a variety of studies linking infectious agent exposure with tubulin antibodies.4 Elevated anti- tubulin antibody levels were found in sera from patients who presented with a number of infections, including leishmaniasis, African trypanosomiasis, onchocerciasis, schistosomiasis and leprosy.1

Tubulin may be altered during the course of an infection, thus rendering it immunogenic. Infectious agents due to antigenic similarity may illicit a cross-reaction autoimmune response.

Tubulin cross-reacts with Streptococcal protein, which can lead to autoimmunity and the neurological dysfunction associated withPANDAS/ANDAS/OCD.7

Tubulin is also a neuronal target of autoantibodies in Sydenham’s Chorea, in which these autoantibodies alter the blood-brain barrier, thus increasing permeability of the blood-brain barrier.3

This event results in cell signaling, dopamine release, and movement and neuropsychiatric abnormalities. Antibodies against nerve cell Tubulin have been demonstrated in patients with toxic chemical exposure, including mercury and other heavy metals.

Anti- tubulin antibodies are also detected in a high ratio of patients with recent onset type 1 diabetes, but decrease or disappear during the course of the disease.6 Anti-tubulin antibody was detected in 56% of patients with Hashimoto’s thyroiditis and in 41% of patients with Graves’ disease.5

CEREBELLAR

Cerebellum is the part of the brain controlling movement and balance. Inside the cerebellar cortex there are large neurons called Purkinje’s cells. The Cerebellar antibodies test measures antibodies against the cerebellum Purkinje’s Cell Antigens

Antibodies Appear

• Autism5
• Celiac Disease 5
• Gluten Ataxia 5, 7
• Opsoclonus-Myoclonus Syndrome 3

Known Cross-Reactions: gliadin, 6-8 tumor cells,3  Milk butyrophilin 6, 7

Clinical Significance:

Elevated Cerebellar antibodies are an indication of neuroautoimmunity. Infection, or exposure to toxic chemicals, can induce production of antibodies against Purkinje’s cells.5

Due to cross-reactivity between Gliadin and Cerebellar antigens or peptides, an autoimmune reaction occurs. 7

Medical conditions related to Purkinje cells range from toxic exposure (mercury, alcohol) to autoimmune disorders (Celiac disease), and from genetic mutations (spinocerebellar ataxias) to neurodegenerative diseases of no known genetic basis (cerebellar multiple system atrophy, sporadic ataxias).

Although the etiology of paraneoplastic cerebellar degeneration (PCD), which generally occurs in patients with neoplasms of the lung, breast, ovary, or with Hodgkin’s disease, is unknown, scientists speculate it is autoimmune in nature.4

The known cross-reactivity between cerebellar peptides and gliadin and milk butyrophilin, as seen in patients with gluten sensitivity, which includes many individuals with autism spectrum disorder (ASD), may be responsible for molecular level gluten ataxia,6 7 tremors and alterations of coordination, balance and sensations.2, 6, 7

Exacerbating cerebellar degeneration, and bringing about the subsequent clinical conditions in ASD patients is mercury –induced disruption in cerebellar synaptic transmission between parallel fibers or climbing fibers of Purkinje cells.2

According to Bernard and colleagues, due to the anti-cerebellar antibodies present in the sera of ASD patients, ongoing damage may arise as these antibodies find and react with neuronal antigens.2

SYNAPSIN

Synapsin I, also known as phosphosynaspin I, is a major immunoreactive protein found in most neurons of the central and peripheral nervous systems. It is a member of a group of neuronal phosphoproteins involved in the regulation of neurotransmitter release.

Synapsin I is present in the nerve terminal of axons, specifically in the membranes of synaptic vesicles.

Antibodies Appear:

• Demyelinating Diseases 2
• Inhibited Neurotransmitter Release 4
• Lupus  4
• Multiple Sclerosis 2

Known Cross-Reactions: Gliadin1,5

Clinical Significance:

Antibodies against Synapsin can contribute to neuronal damage2, 4 as well as non-neuronal tissues.3

There is a similarity between Synapsin I and Gliadin (a protein of wheat) in that they both have high frequencies of proline and glutamine residues, thus, cross-reactivity occurs between Synapsin I and Gliadin.1,5

This molecular mimicry triggers autoimmunity resulting in neurological deficits often associated with gluten sensitivity and, in genetically susceptible patients, with Celiac Disease.

Non-neuronal Synapsin I has also been identified in the liver and is thought to be associated with the trans-Golgi network-derived compartment.3

This placement suggests that Synapsin I plays a role in modulating post-trans-Golgi network trafficking pathways of secreted proteins.3