The American Academy of Neurology will be meeting in Philadelphia from April 26-May 3. In advance of this meeting, some press releases are being sent out. Apparently, the BIG NEWS in MS research is KIR4.1 antibodies are present in about half of the plasma samples from patients with a pre-clinical diagnosis of MS patients, and this could be a diagnostic and treatment target. According to research by the Technical University in Munich-
The researchers found that KIR4.1 antibody titers were significantly higher for pre-clinical MS patients than healthy controls (P = 0.0185). Seven of the pre-clinical patients were considered KIR4.1 antibody positive, while two had borderline activity and seven were found to be negative. All healthy controls were also KIR4.1 antibody negative. In the longitudinal analysis, pre-clinical MS patients had KIR4.1 antibodies several years prior to the first clinical attack. In individual pre-clinical MS patients, antibody titers varied at different time points. There was no significant difference in titers before and after disease onset
But research into KIR4.1 antibodies is not new....nor is it exclusive to MS.
We see the same immune reaction to KIR4.1 in hydrocephalus and cerebral edema.
A paper published in the New England Journal of Medicine in 2012 was the first research to identify the immune reaction to KIR4.1 in MS.
Researchers tested the IgG levels in the blood of people with MS and found a very specific reaction to the protein KIR4.1.
And the researchers found there was an antibody, or immune system, response to KIR4.1
KIR4.1 is a potassium channel protein which is vitally important to myelination, neuronal plasticity and the inflammatory response. KIR4.1 is a good guy.
Let's get an understanding of what the researchers found. IgG stands for Immunoglobin G, which is the main antibody found in our blood. Antibodies are major componants of the immune system. When something is presented in the body that is seen as foreign, like a virus or bacteria, the immune system goes after the invader, and the white blood cells produce an antibody. This antibody is like a footprint marker leading back to the "invader"---it can tell us what the body sees as foreign. This can also happen if a protein or plasmic particle ends up on the wrong side of the blood brain barrier. It doesn't mean the body is having an "autoimmune reaction." In this case, the body sees the good guy, KIR4.1, as an invader.
We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo.
When KIR4.1 serum IgG was injected into cisternae magnae of mice, there was an alteration of glial fibrillary acidic protein and loss of KIR4.1 expression, suggesting that "multiple sclerosis-specific anti-KIR4.1 serum IgG can recognize its target antigen in the CNS and induce structural damage to glial cells," Hemmer et al say.
In a related editorial, Anne Cross (Washington University, St Louis, Missouri, USA) and Emmanuelle Waubant (University of California, San Francisco, USA) describe KIR4.1 as "an unexpected but plausible antigenic target."
They note that while autoantibodies do not play a primary role in MS pathology, they may perpetuate the breakdown of the CNS, which is a hallmark of the disease.
So, my question is---Where else do we see this happen??
What is going on? Why is this happening? How did KIR4.1 become identified as a bad guy?
And by using pub med, I find out that this reaction towards KIR4.1 occurs in brains with hydrocephalus and edema.
KIR4.1 is a protein which is involved in "water flux" or water transport.
If it shows up where it isn't supposed to, the immune system becomes activated.
In this research, in cytotoxic edema, KIR4.1 becomes "mislocalized." It goes where it should't go. Perhaps it is the involvement of this protein in the break of the blood brain barrier which creates the immune reaction for some in MS, when KIR4.1 appears in brain tissue??
In this paper, KIR4.1 is upregulated in edema.
In normal brain tissue, AQP4 and Kir4.1 were detected around the microvessels. In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain.
In this research, there is immunoreactivity to KIR4.1 in the swollen astrocytes surrounding brain tumors
In normal brain, Kir4.1 was seen around microvessels (fig 1B1B),), in the glia limitans/pia (fig 1E1E),), and in occasional neurones in cortical layers I and II (fig 1E1E insert). In brain contusion (fig 2B2B)) and brain surrounding carcinoma and oligodendroglioma, Kir4.1 expression was also seen around microvessels. Kir4.1 was upregulated in astrocytes in bacterial meningitis (fig 2E2E),), contusion (fig 2B2B),), and in carcinoma (fig 2H2H),), oligodendroglioma (fig 2K2K),), and glioblastoma cells (fig 22N).N). Gemistocytes in glioblastoma showed pronounced Kir4.1 immunoreactivity (fig 2N2N insert).
And in this study in rats with hydrocephalus, there is an immune reaction to KIR4.1
Hydrocephalus is characterized by impaired cerebrospinal fluid (CSF) flow with enlargement of the ventricular cavities of the brain and progressive damage to surrounding tissue. Bulk water movement is altered in these brains. We hypothesized that increased expression of aquaporins, which are water-permeable channel proteins, would occur in these brains to facilitate water shifts. We used quantitative (real-time) RT-PCR, Western blotting and immunohistochemistry to evaluate the brain expression of aquaporins (AQP) 1, 4, and 9 mRNA and protein in Sprague–Dawley rats rendered hydrocephalic by injection of kaolin into cistern magna. AQP4 mRNA was significantly up-regulated in parietal cerebrum and hippocampus 4 weeks and 9 months after induction of hydrocephalus (P < 0.05). Although Western blot analysis showed no significant change, there was more intense perivascular AQP4 immunoreactivity in cerebrum of hydrocephalic brains at 3–4 weeks after induction. We did not detect mRNA or protein changes in AQP1 (located in choroid plexus) or AQP9 (located in select neuron populations). Kir4.1, a potassium channel protein linked to water flux, exhibited enhanced immunoreactivity in the cerebral cortex of hydrocephalic rats; the perineuronal distribution was entirely different from that of AQP4. These results suggest that brain AQP4 up-regulation might be a compensatory response to maintain water homeostasis in hydrocephalus.
Could it be that CCSVI creates venous congestion--a situation akin to normal pressure hydocephalus--with swelling and an interruption in cerebral spinal fluid causing a break in the blood brain barrier, and this activates the immune reaction to KIR4.1??
Here is a recent paper looking at the body's reaction to aquaporins and damage to the brain in other neurodegenerative diseases, including NMO and Alzheimer's.
Thus, it is reasonable to predict that changes in potassium channel (Kir 4.1 channels) function may alter brain homeostasis leading to brain impairment. Water movement via the AQP4 water channel localized to astrocyte end-feet maintains osmotic balance and promotes effective potassium siphoning .
In a recent paper, Wilcock and colleagues  studied the effects of amyloid accumulation at cerebral vessels on the NVU, using a transgenic mouse model that show amyloid deposition, tau pathology and neuronal loss. Transgenic mice with high levels of CAA have significant reductions in AQP4 and Kir4.1 positive staining associated with the blood vessels. A potential explanation for the loss of AQP4 and Kir4.1 channels is that they share a common anchoring protein that is affected by vascular amyloid deposition: the Dp71 dystrophin protein, localized on perivascular astrocytes . Dystrophin is associated with dystroglycan, which in turn, associates with syntrophins: genetic deletion of syntrophin has resulted in mislocalization of AQP4  and decreased perivascular Kir4.1 channel expression . Thus, changes in dystrophin levels and function may, in part, explain the loss of AQP4 from the astrocyte end-feet as well as the reduction in levels of Kir4.1 channels in mice that express high levels of CAA. Moreover, in support to this hypothesis, Wilcock and colleagues found that gene expression of Kir4.1, AQP4 and dystrophin were significantly reduced also in human post-mortem diagnosed AD brain with moderate and severe CAA.
Together, these findings show increased expression of water channels in the brain in human and animal prion diseases that may have implications in the regulation of water transport in astrocytes and may account for an imbalance in water and ion homeostasis. Although change in AQPs expression may be a secondary change of TSE pathologies, it may reflect important aspects of astrocytic pathology associated with these diseases.
Which means the immune reaction to KIR4.1 in MS could very well be a secondary reaction, due to changes in the water channels in the MS brain--and not "auto-immune."
The discovery of this antigen does not mean it is a primary reaction. Nor does it mean that blocking the antigenic response will help people with MS. The fact that it is not found with 100% specificity in MS means there are more questions about the relevance of this discovery.
MS researchers--we beg you, ask the big questions, look at the big picture.
If lay people can do this, surely you should be able to, as well.
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