CD244 – Rheumatoid Arthritis

CD244, an immunoregulatory receptor encoded by HGNC:18171, has been evaluated in the context of rheumatoid arthritis (RA) (MONDO:0008383). Although CD244 plays a well‐established role in immune cell signaling, current genetic investigations suggest that its direct contribution to RA susceptibility is limited.

In a large UK case‑control study involving 3962 RA patients and 3531 controls (PMID:19435719), a robust association was replicated for CD40, while the CD244 marker (rs6682654) did not show significant association with RA. This negative result was further supported by a subsequent study evaluating shared autoimmune risk loci in systemic sclerosis, which also failed to implicate CD244 in RA pathogenesis (PMID:21586211).

The genetic evidence for RA is further weakened by the absence of compelling rare or pathogenic variants in CD244—no valid coding change in HGVS format (e.g., one starting with “c.” and properly formatted) could be identified from the available reports. Moreover, segregation analyses across affected relatives in familial cases have not provided additional supportive evidence.

On the functional front, multiple studies in alternative disease contexts have confirmed the role of CD244 in modulating immune responses. For example, functional assays in a melanoma model demonstrated that disruption of CD244 alters natural killer cell responses (PMID:15634901), and studies in hemophagocytic lymphohistiocytosis further highlighted its immunomodulatory importance (PMID:24985396). Despite these corroborative findings regarding immune cell function, no studies have established a direct mechanistic link between CD244’s functional alterations and RA pathogenesis.

In sum, while CD244 remains a biologically important molecule in immune regulation, the current genetic and segregation data do not support a major pathogenic role in rheumatoid arthritis. The discrepancy between its clear functional impact in other immunoinflammatory conditions and the lack of genetic association in RA underscores the complexity of multifactorial autoimmune diseases.

Key take‑home: Although CD244 is critical for immune cell function, its limited genetic evidence in RA makes it an unlikely diagnostic marker for the disease.

References

• Annals of the rheumatic diseases • 2010 • Association of CD40 with rheumatoid arthritis confirmed in a large UK case‑control study PMID:19435719
• Clinical and experimental rheumatology • 2011 • Association study of 3 rheumatoid arthritis risk loci in systemic sclerosis in European Caucasian population PMID:21586211
• Journal of immunology • 2005 • Targeted disruption of the 2B4 gene in mice reveals an in vivo role of 2B4 (CD244) in the rejection of B16 melanoma cells PMID:15634901
• The Journal of allergy and clinical immunology • 2014 • Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis PMID:24985396

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