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Small study begins to uncover the role of antibodies to KIR4.1 in MS
Major finding: Anti-KIR4.1 antibodies were found in plasma from 7 of 16 patients several years before they developed MS, compared with none of 16...
Contrary to findings from previous studies, serologic testing for KIR4.1-specific IgG did not help in the diagnosis of multiple sclerosis in a new comparative study.
"No neural autoantigen has been clinically validated as a target of immunoglobulins in serum or CSF [cerebrospinal fluid] in multiple sclerosis," researchers led by Adipong Brickshawana, Ph.D., wrote July 7 in the Lancet Neurology. "The absence of a disease specific biomarker to aid multiple sclerosis diagnosis makes therapeutic trial design and outcome interpretation difficult," they said.
In their own analysis, the researchers determined that the lack of patient-derived IgG reactivity with KIR4.1 "in plasma membrane, cytoplasm, or endoplasmic reticulum of cultured glia argues against antigenic differences in recombinant and native glial KIR4.1." The finding runs counter to 2012 study that used enzyme-linked immunosorbent assay (ELISA). It found that serum antibodies against KIR4.1 were detected in 47% of 397 patients with multiple sclerosis, 1% of 329 patients with other neurologic diseases, and none of the 59 healthy donors (N. Engl. J. Med. 2012;367:115-23).
For the current analysis, Dr. Brickshawana of the departments of immunology and neurology at the Mayo Clinic, Rochester, Minn., and his associates used ELISA with a KIR4.1 peptide to test archival serum from 229 population-based and 57-clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, as well as CSF from 25 patients with multiple sclerosis and 22 disease controls (Lancet Neurol. 2014 July 7 [doi:10/1016/S1474-4422(14)70141-3]).
The researchers used cell-based immunofluorescence and immunoprecipitation to test all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1. They also looked for KIR4.1 immunoreactivity in archival brain samples from 15 patients with multiple sclerosis confirmed by histopathology, as well as from three controls with non-neurologic diseases.
Of the serum samples collected, only three from the 286 patients with multiple sclerosis (1.05%) and two from the 208 controls (0.96%) demonstrated KIR4.1 reactivity on ELISA, while none of the CSF samples from patients or controls demonstrated KIR4.1 reactivity. In addition, the researchers did not detect KIR4.1 loss from glia in supratentorial white-matter lesions of archival multiple sclerosis cases.
"Our findings provide neither serological nor neuropathological evidence to lend support to the idea that autoantibodies target glial KIR4.1 K+ channels in patients with multiple sclerosis," the researchers concluded.
Dr. Brickshawana and his colleagues went on to note that different analytical approaches "might, in part, explain these contradictory findings. However, before drawing conclusions, it is essential that KIR4.1 immunoreactivity is examined relative to control white-matter expression as we did in the current study."
The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic’s Robert and Arlene Kogod Center on Aging.