Potassium Channel KIR4.1
as an Immune Target
in Multiple Sclerosis
KIR4.1 – Possible Relevance to MS
• KIR4.1 expression
– An ATP-sensitive inward rectifying potassium channel sub-unit
– Critical to the development of oligodendrocytes and myelination
• Involved in the maintenance of the electro-chemical
gradient across the cell membrane of perisynaptic
astrocytes
KIR4.1 – Possible Relevance to MS
• Possible interaction between KIR4.1 and AQP4 at
perivascular astrocyte processes that regulates water
homeostasis
• In humans, mutations in the gene encoding KIR4.1
associated with the development of EAST or SeSAME
syndrome (characterized by epilepsy, ataxia,
tubulopathy, and sensorineural deafness)
Study Design
• Objective: To identify/characterize serum IgG
specific to MS
• MS/CIS patients (n=397)
– MS patients diagnosed according to the 2005 McDonald
criteria
– CIS patients had > 1 episode compatible with MS relapse
and >2 lesions on MRI, oligoclonal bands in the
cerebrospinal fluid, or both
• 2 control groups (n = 388)
– Patients with other neurologic diseases (n=329)
– Age-matched healthy individuals (n=59)
Srivastava R, et al. N Engl J Med. 201;367:115-123
Results
Specificity of Anti-KIR4.1 Antibodies for MS
• Serum levels of anti-KIR4.1 antibodies significantly
higher in patients with MS (46.9%) than in patients with
other neurologic diseases (0.9%) and in healthy
individuals (0%) (P<.001 for both comparisons)
• No significant differences in anti-KIR4.1 antibodies
among patients with CIS, RRMS, and progressive MS
Srivastava R, et al. N Engl J Med. 201;367:115-123.
Results
Specificity of Anti-KIR4.1 Antibodies for MS
• PBS or serum-depleted of anti-KIR4.1 antibodies
injected into the cisternae magnae resulted in a normal
pattern of glial fibrillary acidic protein (Gfap) and KIR4.1
expression, with KIR4.1 expressed in astrocytes and
oligodendrocytes
• Injections of KIR4.1-reactive serum IgG resulted in
altered Gfap expression, loss of KIR4.1 expression
(particularly in the area of the subarachnoid space), and
deposits of C9neo (a marker of complement activation)
in regions of KIR4.1 depletion
Srivastava R, et al. N Engl J Med. 201;367:115-123.
Conclusions
• Anti-KIR4.1 antibodies exist in some patients with MS
• These antibodies react with KIR4.1 protein expressed on
glial cells and may induce structural damage to glial cells
• Anti-KIR4.1 antibodies may contribute to the
development of MS by
– Depleting KIR4.1 on glial cells and altering expression of Gfap in
astrocytes
– Inducing antibody-dependent cell-mediated cytotoxcitiy
– Interfering with the channel function of KIR4.1, negatively
effecting potassium buffering and neurotransmitter homeostasis
Srivastava R, et al. N Engl J Med. 201;367:115-123.
Conclusions
• Perhaps the discovery of these autoantibodies in
sub-groups of MS patients will assist in defining their
prognosis and perhaps their response to treatment
• This study represents a break-through by considering
a broader set of autoantibodies beyond those against
myelin and EAE, and looking for new autoantibody
reactivity
Abbreviations: EAE, experimental autoimmune encephalitis
Srivastava R, et al. N Engl J Med. 201;367:115-123.
Conclusions
• Since only 47% of MS patients have serum anti-KIR4.1
antibodies, this provides a basis for identifying other
targets of the immune response in MS and assessing the
impact of these reactivities on treatment and disease
prognosis
Abbreviations: EAE, experimental autoimmune encephalitis
Srivastava R, et al. N Engl J Med. 201;367:115-123.