Time to put Kir4.1 as a major autoimmune target to bed…it isn’t

Pröbstel AK, Kuhle J, Lecourt AC, Vock I, Sanderson NS, Kappos L, Derfuss T. Multiple Sclerosis and Antibodies against KIR4.1. N Engl J Med. 374:1496-8.

Chastre A, Hafler DA, O’Connor KC. Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med. 2016 14;374(15):1495-6.

The search for specific autoantibodies in patients with multiple sclerosis has been an area of intensive research for decades, but the unequivocal identification of one or several autoantigens associated with the disease has remained elusive. 

However, considerable interest has been raised by a study showing the presence of serum autoantibodies to KIR4.1, an astrocytic inward-rectifying potassium channel, in 47% of adult patients with multiple sclerosis but not in patients with other neurologic diseases or in healthy controls. 

However, subsequent independent studies that were performed with the use of a cell-based assay or peptide antigen–based enzyme-linked immunosorbent assay (ELISA) have not corroborated these findings..

On study tested the original method used with 141 pwMS and 131 controls and got nothing interesting.

In the other study a commonality among the studies that have contradicted the original report is that one of the three approaches that were originally used to measure the autoantibodies, a protein antigen–based ELISA, was not used. 

Here the other study made the channel which contains four subunits and had a positive control and then tested the activity in 86 pwMS…...No difference for most people..end of story. 

There experiences found technical challenges methodologies but suggest that people doing these types of study should create replicate samples, that can be provided for replicate experiments by totally independent groups. Then we will more quickly dissect fact from fiction.

How come two papers arise at the same time, either they were talking to each other after one showed the data and the other said hey we have the same data, or maybe one was reviewing the other and said hey we have the same data. However two more agreements and the original data seems more and more on thin ice.

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  • "The search for specific autoantibodies has been an intensive area of research for decades…. " For decades??? Please, when the auto antigen has been found then it will be an autoimmune disease. What other disease has such a track record of futility in finding its origin? I remember hearing Dr. Stephen Hauser speak and he stated that MS and HIV have seen the greatest advances in the last twenty years. Although I would not put MS in the same category as HIV as the latter may lead to AIDS with a high mortality. But I can see the end of HIV on the not too distant horizon. With MS we are still stuck with the usual suspects: vit D, EBV, smoking, etc. Maybe depletion of B cells using Alemtuzumab will be a cure.

    • Track record of futility….Rheumatoid arthritis type I diabetes, psoriasis etc etc etc. What autoimmune disease do we know the target for?
      One thing you should ask when comparing the HIV and Ms. How much resource has gone into HIV verses Ms? Alot more for HIV and it is a tractable problem put the same resource into dealing with JC virus and PML will become a thing of the past perhaps

  • Re: what other diseases have yet to yield a cause. Parkinson's,Alzheimers and ALS are well known examples.

    • Some ALS (10% but may actually be an undestimate) cases have been shown to have a genetic link SOD-1 mutation and C9Orf72 (present in my family).
      Same is true with familal (15%) cases of Parkinsons with mutations in LRRK2, PARK2, PARK7, PINK1, or SNCA.

  • By definition, the presence of specific autoantibodies is a prerequisite for a disease to be called autoimmune. No such autoantibodies have been found in MS, yet the WHOLE system that lives out of MS treats it like an autoimmune disease. On what grounds? On the "fact" that immune suppressing and modulating drugs reduce inflammation. But the only thing proven by that is that the immune system is at works in the CNS. It says nothing as to whether the CNS tissue is damaged beforehand or by the action of the immune system itself. What is worse, no one is interested in finding out.

    Time is brain, but let as examine all possible autoantibodies before we untag MS. It won't take long, just a century or two…

    • Hi VV
      Remember that T cells (and despite the resurgence of the B cell at the moment, they're still important) don't make antibodies.
      Plenty of people are interested the root cause of MS, whether the immune system involvement is primary or secondary to some event in the CNS is something we'd all love to finally know.

  • I think the time has come to realize the immune system is not an independent system that functions autonomously on it's own. All people have autoreactive immune cells so looking for a target is a fruitless endeavor. The nervous system has control over the immune system as it does for every system in your body. Here lies the problem.

  • I am afraid that the author of this article is confusing specificity and sensitivity. An autoantibody can be considered specific even if just one person has it, as long as no healthy control has it.

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