Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

Clin Exp Immunol. 2011 Dec;166(3):338-45. doi: 10.1111/j.1365-2249.2011.04484.x.


It has long been known that tumour necrosis factor (TNF)/TNFRSF1A signalling is involved in the pathophysiology of multiple sclerosis (MS). Different genetic and clinical findings over the last few years have generated renewed interest in this relationship. This paper provides an update on these recent findings. Genome-wide association studies have identified the R92Q mutation in the TNFRSF1A gene as a genetic risk factor for MS (odds ratio 1·6). This allele, which is also common in the general population and in other inflammatory conditions, therefore only implies a modest risk for MS and provides yet another piece of the puzzle that defines the multiple genetic risk factors for this disease. TNFRSF1A mutations have been associated with an autoinflammatory disease known as TNF receptor-associated periodic syndrome (TRAPS). Clinical observations have identified a group of MS patients carrying the R92Q mutation who have additional TRAPS symptoms. Hypothetically, the co-existence of MS and TRAPS or a co-morbidity relationship between the two could be mediated by this mutation. The TNFRSF1A R92Q mutation behaves as a genetic risk factor for MS and other inflammatory diseases, including TRAPS. Nevertheless, this mutation does not appear to be a severity marker of the disease, neither modifying the clinical progression of MS nor its therapeutic response. An alteration in TNF/TNFRS1A signalling may increase proinflammatory signals; the final clinical phenotype may possibly be determined by other genetic or environmental modifying factors that have not yet been identified.

MeSH terms

  • Fever
  • Genome-Wide Association Study
  • Hereditary Autoinflammatory Diseases / genetics*
  • Hereditary Autoinflammatory Diseases / metabolism
  • Hereditary Autoinflammatory Diseases / pathology
  • Humans
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Nervous System Diseases / genetics
  • Nervous System Diseases / metabolism
  • Polymorphism, Single Nucleotide
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / cerebrospinal fluid
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / immunology


  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • Tumor Necrosis Factor-alpha

Supplementary concepts

  • Periodic fever, familial, autosomal dominant