Complex Link Between Immunity and Thyroid Health (CD40)

The CD40 (cluster of differentiation 40) gene encodes for a protein present on the surface of specific immune cells (antigen-presenting cells). This protein acts as a receptor and activates the cells, causing a range of downstream effects, such as their maturation and development [R].

CD40 belongs to the family of TNF receptors and plays a fundamental role in B-cell activation. It causes B cell to mature and produce large amounts of high-affinity (specific) antibodies [R, R].

Did you know? Although CD40 mostly acts as a surface receptor, it can reach the cell nucleus and affect gene expression [R].

Future Target for Autoimmunity Drugs?

Although CD40-mediated activation is a crucial component in the immune response, it can also play a role in different autoimmune conditions. By introducing antibodies to CD40 ligand, scientists were able to relieve the following autoimmune conditions in animal studies [R, R, R]:

• Graves’ disease
• Rheumatoid arthritis
• Lupus nephritis (kidney disease)
• Myasthenia gravis (muscle weakness)
• Mercury-induced immunity

Still, the research in this area is young and lacks confirmation in clinical trials.

Based on its role in antibody production and immune response, researchers have studied CD40 as a candidate gene for autoimmune thyroid disorders. Indeed, they found a potential link with Graves’ disease (GD) or autoimmune hyperthyroidism [R].

A single CD40 variant, rs1883832, showed association with GD in different trials, but the initial results were conflicting [R].

A meta-analysis gathered the data from over 4,000 participants of mixed ethnicity to cast more light on this link. According to the results, Graves’ disease was 22% more common in people with the “CC” genotype. It had a much higher impact on Korean subjects, but the data for this population were limited [R].

A 2019 meta-analysis of 17 studies and nearly 9,000 Chinese people came to similar conclusions: those carrying the “T” allele were less likely to develop GD. The observed effect was stronger compared with European studies, and the variant also showed an association with Graves’ ophthalmopathy (eye complications) [R].

When it comes to Japan, one study found the same connection while another did not. Japanese carriers of the “C” allele appear to have milder forms of Graves’ disease (GD), and they develop the condition later [R, R, R].

Initially, scientists didn’t observe a link between rs1883832 and other autoimmune disorders, and they considered this variant GD-specific. However, later research has revealed a potential association of the “T” allele with [R, R, R]:

• Crohn’s disease
• Multiple sclerosis
• Giant cell arteritis

A single CD40 variant, rs1883832, correlates with Graves’ disease in European and Asian populations. It has a particularly strong impact on Chinese and Korean descendants and may also correlate with Graves’ ophthalmopathy (eye complications).

Key Mechanisms at Play

Researchers located the C/T polymorphism at rs1883832 in a so-called Kozak sequence, essential for protein synthesis. The “C” allele speeds up the process by 15-30%, resulting in higher CD40 receptor expression [R, R].

In turn, B-cells with more CD40 and other co-stimulatory receptors are easily activated and more prone to an autoimmune response [R, R].

Studies on the cells from GD patients have found higher CD40 expression on thyroid cells, which can sometimes act as antigen-presenting cells, too [R, R].

In terms of downstream effects on the immune response, excess CD40 may cause over-production of inflammatory cytokines such as IL-6 and thus promote thyroid inflammation and autoimmunity [R, R].

The “C” allele at rs1883832 can increase CD40 receptor expression and cause over-production of inflammatory IL-6. This mechanism may contribute to thyroid inflammation and autoimmunity.

You can see your genotype for key CD40 SNPs in the table below. However, keep in mind that these results are based on association studies, and more research will be needed to know what role (if any) these variants play in actually causing thyroid disorders. Also, many different factors — including other genetic and environmental factors — can influence thyroid health. Therefore, just because you have one of these genotypes does not necessarily mean you are at an increased risk of developing a thyroid disorder!

SNP Table

SNP Summary

Primary SNP:

CD40 rs1883832

• “C” – correlates with higher rates of Graves’ disease
• “T” – doesn’t correlate with Graves’ disease

Population Frequency

Over 52% of European descendants have the “problematic” CC genotype, so there’s no reason to worry. This genotype is less common in East Asian (31%) and much more common in African populations (95%).