[Why C-reactive protein is (usually) not high in SLE].

Area of Science:

• Immunology
• Rheumatology
• Biochemistry

Background:

• Elevated C-reactive protein (CRP) in systemic lupus erythematosus (SLE) often indicates infection rather than active disease.
• Interleukin-6 (IL-6) is a key stimulator of CRP, and its levels are typically high during active SLE, posing an intriguing paradox.

Purpose of the Study:

• To elucidate the mechanism behind the dissociation of high IL-6 levels and normal CRP levels in active SLE.
• To explain why CRP is a more reliable marker for bacterial infections than for SLE disease activity.

Main Methods:

• Investigated the interaction between IL-6 and interferon-alpha (IFNα) in the context of SLE.
• Examined the shedding of the IL-6 receptor from cell membranes.
• Assessed the buffering capacity of soluble IL-6 receptors in plasma.

Main Results:

• Interferon-alpha (IFNα) in combination with IL-6 induces the enzymatic cleavage and shedding of the IL-6 receptor from cell membranes.
• These soluble IL-6 receptors act as a buffer, inhibiting IL-6's biological activity in plasma.
• This buffering effect prevents IL-6 from stimulating hepatocytes to produce CRP, even when IL-6 levels are elevated in SLE.

Conclusions:

• The shedding of IL-6 receptors, triggered by IFNα and IL-6, explains the uncoupling of IL-6 and CRP levels in SLE.
• CRP production is only observed when IL-6 levels are extremely high, exceeding the buffering capacity, which typically occurs during severe infections or rarely in lupus serositis or arthritis.