Polymorphisms of innate pattern recognition receptors, response to interferon-beta and development of neutralizing antibodies in multiple sclerosis patients.
BACKGROUND
Interferon-beta therapy of patients with relapsing-remitting multiple sclerosis involves repeated 'immunizations' with exogenous protein solutions. Innate pattern recognition receptors play an important role in immune responses towards foreign substances and may thus be related to treatment outcome.


OBJECTIVE
To determine the genotypes at 42 single nucleotide polymorphism loci in selected pattern recognition receptors for 567 prospectively followed relapsing-remitting multiple sclerosis patients treated with recombinant interferon-beta, and test for relationships to several outcome parameters, including formation of interferon-beta neutralizing antibodies.


RESULTS
The results suggest an association between the rs5743810 polymorphism (Ser249Pro) of TLR6 and development of neutralizing antibodies after 24 months of therapy in males (p = 0.00002), but not in females (p = 0.2). This association survived crude Bonferroni correction (p (corrected) = 0.02). Additional associations were observed in carriers of the TLR2-rs5743708 and NOD2-rs3135499 SNPs (time to relapse), the TLR7-rs179008 and NOD1-rs2075820 SNPs (time to disease progression) and the TLR4-rs7873784, TLR9-rs5743836, and NOD2-rs2066842 SNPs (frequency of neutralizing antibodies development). All of these, however, failed to survive correction for multiple testing. There were no significant differences between interferon-beta responders and non-responders for any of the investigated single nucleotide polymorphisms.


CONCLUSIONS
The rs5743810 polymorphism of TLR6 may be involved in development of anti-interferon-beta antibodies in males, although further studies are required to firmly establish this.
Enevold
Christian
C
Institute for Inflammation Research, Department of Rheumatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. chrej@hotmail.com
Oturai
Annette B
AB
Sørensen
Per Soelberg
PS
Ryder
Lars P
LP
Koch-Henriksen
Nils
N
Bendtzen
Klaus
K
D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000627:therapeutic use*; D007370:Interferon Type I / Q000276:immunology* / Q000627:therapeutic use*; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics*; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D053633:Receptor, Interferon alpha-beta / Q000276:immunology; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D012737:Sex Factors; D051216:Toll-Like Receptor 6 / Q000235:genetics* / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
D057134:Antibodies, Neutralizing; D007155:Immunologic Factors; D007370:Interferon Type I; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D053633:Receptor, Interferon alpha-beta; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1