**4.3 Cluster of differentiation 40 (CD40)**

The Cluster of Differentiation (CD) are cell surface proteins with each of them assigned a specific number thereby allowing cell phenotypes to be recognized. Surface expression of a particular CD molecule is functional for the characterization of cell phenotypes. These molecules can act either as receptors or ligands. Some CD proteins though do not play role in cell signaling, but do have other functions, such as cell adhesion. CD for humans is numbered upto 371 with their specific functions. CD40 is a costimulatory protein found on the antigen- presenting cells and results in their activation. The binding of CD154 (CD40L) on helper T cells to CD40 activates antigen presenting cells and induces a variety of downstream effects. Deficiency can lead to Hyper-IgM syndrome type3. It is located on chromosome 20 in humans and chromosome 2 in mouse. Disruption of the CD40- CD40L co-stimulatory pathway has been found in many autoimmune diseases, including GD. on the basis of a genome-wide linkage study in GD, *CD40* has been associated with GD as a positional candidate which implicated 20q11 chromosomal region, designated GD-2, as harboring a susceptibility locus [44]. C/T polymorphism (rs1883832) located at position −1 relative to translation start site affects the initiation step of translation as it has a direct effect on kozak sequence. The C allele of *rs1883832* has been found to confer risk of GD among Caucasians whereas the results from in vitro transcription/translation system suggested that this allele predisposes to GD by increasing the efficiency of translation of CD40 mRNA [44]. There is a close association between GD and C variant of *rs1883832* as supported by studies in the Japanese population although in this population the effect may be constrained to patients with the late onset of disease [45] and/or to the CC and CT genotypes, signifying a dominant rather than a recessive model of inheritance [45]. Recently, siRNA mediated inhibition of CD40 expression was evaluated for potential to prevent development of GD in mice immunized with adenovirus expressing human TSHR A subunit. In spite of successful lowering of CD40 expression, no effect on the rate of disease induction was observed [46].
