What is the role of Interleukin-17 (IL-17) in the development of lupus nephritis?

The Role of IL-17 in the Development of Lupus Nephritis

IL-17 plays a critical pathogenic role in lupus nephritis by promoting inflammation, enhancing autoantibody production, and contributing to kidney damage, making it a potential therapeutic target for treatment of this serious complication of SLE.

Pathophysiological Role of IL-17 in Lupus Nephritis

IL-17 Production and Sources

• IL-17 production is abnormally increased in patients with systemic lupus erythematosus (SLE), particularly in those with lupus nephritis 1
• In SLE patients, CD3+CD4-CD8- (double negative) T cells and CD4+ T cells are important sources of IL-17 1
• Early in the development of autoimmunity, innate immune cells including neutrophils (Ly6G+) and macrophages (F4/80+) are predominant sources of IL-17A 2
• IL-17-producing T cells have been identified in kidney biopsies of patients with lupus nephritis 1

Mechanisms of IL-17-Mediated Kidney Damage

• IL-17 amplifies immune responses by:
  • Increasing local production of chemokines and cytokines 1
  • Recruiting neutrophils and monocytes to target organs 1, 3
  • Augmenting production of autoantibodies, particularly anti-dsDNA antibodies 4, 2
  • Aggravating inflammation and damage in the kidneys 1, 3
• IL-17 contributes to immune complex deposition and complement activation in the kidney 4
• IL-17 expression in renal tissue is found within inflammatory infiltrates 5

Clinical Correlation and Prognostic Value

Association with Disease Severity

• Serum IL-17 levels positively correlate with the severity of lupus nephritis, as evaluated by:
  • Histopathological findings in kidney sections 4
  • Proteinuria levels 4
  • Persistence of active nephritis (WHO class III, IV, V) after treatment 5

Predictive Value for Treatment Response

• High baseline IL-17 levels predict an unfavorable histopathological response to treatment 5
• Elevated IL-23 (which promotes IL-17 production) at follow-up is associated with non-response to treatment as measured by BILAG index 5
• A subset of lupus nephritis patients appears to have a Th17-predominant phenotype that may influence response to standard immunosuppressive therapy 5

Experimental Evidence Supporting IL-17's Role

Animal Models

• Enforced expression of IL-17 using adenovirus constructs enhances the severity of lupus nephritis in experimental models 4
• Blockade of IL-17 using neutralizing antibodies results in decreased severity of lupus nephritis 4
• IL-17-deficient mice show impaired induction of lupus nephritis 4, 2
• In pristane-induced lupus models, absence of IL-17A leads to:
  • Decreased levels of IgG and anti-dsDNA antibodies 2
  • Reduced glomerular IgG and complement deposition 2
  • Fewer CD4+ T cells in glomeruli 2
  • Decreased expression of Th1-associated inflammatory mediators 2
  • Attenuated proteinuria and renal injury 2

Therapeutic Implications

Potential for IL-17-Targeted Therapy

• Several IL-17A pathway inhibitors have advanced into clinical trials for autoimmune diseases 3
• Anti-IL-17A monoclonal antibodies and anti-IL-17RA monoclonal antibodies have shown success in phase II trials for multiple autoimmune diseases including:
  • Psoriasis
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Multiple sclerosis
  • Non-infectious uveitis 3
• Anti-IL-17 therapy may represent a promising approach for treatment of lupus nephritis, particularly in patients with a Th17-predominant phenotype 3, 5

Neutrophilic Inflammation and IL-17

• Neutrophilic inflammation in certain conditions is predominantly driven by IL-17 6
• However, data from clinical trials with anti-IL-17 agents in other inflammatory conditions have shown mixed results 6
• A pivotal randomized, placebo-controlled double-blind trial with brodalumab (anti-IL-17 agent) in moderate to severe asthma showed disappointing results 6

Clinical Considerations

Monitoring Disease Activity

• Current guidelines for lupus nephritis management do not specifically address IL-17 monitoring 6
• Standard monitoring includes:
  • Serum creatinine, urinalysis, proteinuria, and blood pressure 6
  • Anti-dsDNA antibody titers, which sometimes correlate with disease activity and active renal disease 6
  • Complement levels, which are sometimes associated with active disease 6

Treatment Approach

• Current treatment guidelines for lupus nephritis focus on conventional immunosuppressive therapies rather than IL-17-targeted approaches 6
• Treatment is based on histological classification and includes:
  • Glucocorticoids and immunosuppressive agents for Class III and IV lupus nephritis 6
  • Hydroxychloroquine as background therapy for all SLE patients with nephritis 6
  • Blockade of the renin-angiotensin system for patients with proteinuria ≥0.5g per 24 hours 6

Future Directions

• Further research is needed to determine if IL-17 levels could serve as a biomarker for:
  • Disease activity in lupus nephritis 5
  • Prediction of treatment response 5
  • Selection of patients who might benefit from IL-17-targeted therapies 3, 5
• Clinical trials specifically evaluating anti-IL-17 therapies in lupus nephritis are warranted 3