Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene.
TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse.
Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation.
Here, we discuss the genetic, experimental and clinical studies on the role of CD40 and CD40L interactions in EAE and MS and we explore novel approaches to therapeutically target this dyad to combat neuroinflammatory diseases.
CD40-CD154 interaction is critically involved in autoimmune diseases, and CD4 T cells play a dominant role in the Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS).
Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.
Our analysis revealed that individuals possessing CT and TT genotypes (predisposing to MS) had decreased level of CD40 mRNA in comparison to those with CC.
Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13-14 in addition to the well established allele HLA-DR15.
The normal effect of CD40 stimulation that up-regulates BDNF secretion levels and induces neuroprotection was absent in the MS patients, while the expression of CD40 on their monocytes was elevated.
Although these subtle differences indicate functional consequences in the immune stimulatory capabilities related to the CD40 C/T(-1) polymorphism, our population-based study found no association with disease susceptibility or disease course in MS.
CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis.
Since interference with CD40/CD40L is an effective way to interfere with autoimmune model diseases such as experimental autoimmune encephalomyelitis, it may be relevant to investigate further the role of these molecules in the pathogenesis of MS.