1. Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis

2. 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 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

3. 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) 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)

4. 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) 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

5. 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 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.

6. 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 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.

7. 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 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.

8. 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 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.

9. 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.