Sunday, 13 July 2014

Autoimmune target bites the dust.

Brickshawana et al. Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study. Lancet Neurol. 2014 Jul. pii: S1474-4422(14)70141-3.

BACKGROUND: Antibodies have been implicated in the pathogenicity of multiple sclerosis by findings of immunoglobulins in patients' CSF and often IgG and complement in lesions, and by a 2012 report that nearly half of patients' serum samples contain IgG specific for a glial potassium-channel, KIR4.1. We aimed to establish the frequency of KIR4.1-binding IgG in serum and CSF of patients with multiple sclerosis, and whether KIR4.1 immunoreactivity is retained or lost in demyelinating lesions.


METHODS: Using ELISA with a KIR4.1 peptide, we tested archival serum from 229 population-based and 57 clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, and CSF from 25 patients with multiple sclerosis and 22 disease controls. We tested all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1, using cell-based immunofluorescence and immunoprecipitation (solubilised recombinant human KIR4.1). We assessed KIR4.1 immunoreactivity in archival brain samples from 15 patients with histopathologically confirmed multiple sclerosis (22 plaques [eight early active, eight inactive, and six remyelinated], 13 periplaque regions and eight normal-appearing white-matter and grey-matter regions) and from three controls with non-neurological diseases.


FINDINGS: Three of 286 serum samples from patients with multiple sclerosis and two of 208 serum samples from controls showed KIR4.1 reactivity on ELISA; none of the CSF samples from patients or controls showed KIR4.1 reactivity. IgG in none of the 50 serum samples from clinic-based patients immunoprecipitated KIR4.1, but a commercial KIR4.1-specific control IgG did. By immunofluorescence, one of 50 serum samples from patients with multiple sclerosis yielded faint plasmalemmal staining on both KIR4.1-expressing and non-expressing cells; 16 bound faintly to intracellular components. In all cases, IgG binding was quenched by absorption with liver powder or lysates from non-transfected cells. Binding by the KIR4.1-specific control IgG was quenched only by lysates containing KIR4.1. IgG in none of the 25 CSF samples from patients with multiple sclerosisbound to KIR4.1-transfected cells. Glial KIR4.1 immunoreactivity was increased relative to expression in healthy control brain in all active demyelinating lesions, remyelinated lesions, and periplaque white matter regions.


INTERPRETATION: We did not detect KIR4.1-specific IgG in serum or CSF from patients with multiple sclerosis or KIR4.1 loss from glia in multiple sclerosis lesions. Serological testing for KIR4.1-specific IgG is unlikely to aid diagnosis of multiple sclerosis. 





So a few years ago it was claimed that an immune target was found and about half of MSers reacted to a channel. 

Find the cause...find a cure.

But the original results were not repeated in another study and again in this study the original idea is questioned. This is the nature of science and you have to spend a lot more time and effort knocking down an dodgy idea than building one. 

The big question is what is the technical differences between the studies.

Myelin basic protein is still the favourite of many. Will it span the test of time? 

6 comments:

  1. Is it your favourite mouse doc? What you place your bets on?

    ReplyDelete
  2. Is the consensus opinion that MS is an autoimmune disease still accepted in the MS research circles?http://www.hindawi.com/journals/ad/2012/969657/
    Can an autoimmunity be defined without an identifiable autontigen/antibody?
    Can the disease be induced by the autoantigen? The authors of the paper point out that multiple antigens (MOG, MBP, PLP) must be administered to elicit a immunologic response instead of one primary antigen. Can autoimmunity follow from an immune dysfunction due to a chronic infectious trigger? Because your research team is focused on latent EBV it suggests you are not a proponent of autoimmunity.

    ReplyDelete
    Replies
    1. yes, yes probably, yes probably, yes,
      Lastly you are making too many assumptions about we do and don't do.

      Delete
    2. Nothing wrong with the truth: "we just don't know....yet"

      Delete
  3. Does the presence of oligoclonal bands in CNS suggest multiple antigens? Will a single antigen result in a single antibody (monoclonal?) rather than multiple antibodies (with different charges/masses) in oligoclonal bands?

    ReplyDelete

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