Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis.

Area of Science:

• Immunology
• Autoimmunity
• Rheumatology

Background:

• Autoimmune arthritis arises from interactions between autoreactive T cells and environmental factors.
• SKG mice, with a ZAP-70 mutation, exhibit altered T cell selection and spontaneous autoreactive T cell production, leading to arthritis upon β-glucan exposure.

Purpose of the Study:

• To investigate the role of the innate immune receptor Nod2 in regulating autoimmune arthritis in SKG mice.
• To elucidate the mechanisms by which Nod2 influences T cell responses and disease pathogenesis.

Main Methods:

• Generated and analyzed Nod2-deficient SKG mice (Nod2-/-SKG) to assess arthritis development and severity.
• Examined T helper 17 (Th17) cell populations, cytokine production (IL-17A, TNF, GM-CSF, IL-22), and regulatory T cell function.
• Assessed the arthritogenic potential of CD4+ T cells from Nod2-deficient mice via adoptive transfer.

Main Results:

• Nod2 deficiency in SKG mice led to significantly exacerbated arthritis, independent of sex and microbiota.
• Arthritis exacerbation was associated with increased Th17 cell expansion and elevated IL-17A levels in joint fluid.
• Neutralizing IL-17A ameliorated arthritis in Nod2-/-SKG mice, confirming Nod2's protective role via Th17 suppression.
• Nod2 deficiency enhanced the intrinsic ability of SKG CD4+ T cells to produce IL-17 and transfer arthritis.

Conclusions:

• Nod2 acts as a critical endogenous suppressor of autoimmune arthritis in SKG mice.
• Nod2 functions intrinsically within T cells to negatively regulate Th17 responses and limit arthritogenic T cell activity.
• Targeting Nod2's regulatory function in autoreactive T cells may offer novel therapeutic strategies for arthritis treatment.