Neuroimmune appendicitis

Lancet. 1999 Aug 7;354(9177):461-6. doi: 10.1016/S0140-6736(98)10463-4.


Background: 15-25% of appendices removed from patients with suspected appendicitis appear normal on histological examination. The cause of pain in such patients is unknown. Since the content of neuropeptides seems to be altered in chronic inflammation, we investigated possible changes in peptidergic innervation for substance P (SP), vasoactive intestinal peptide (VIP), and growth-associated protein-43 (GAP-43).

Methods: Appendices classified as showing acute appendicitis, non-acute appendicitis (clinical signs of acute appendicitis, but histologically not inflamed), or normal were processed for SP, VIP, and GAP-43 immunocytochemistry. The density of SP immunostaining was assessed by digitised morphometry.

Findings: 31 appendix specimens were studied (16 acute, 15 non-acute). 16 specimens were used as controls. Expression of GAP-43 was increased in the non-acute appendices. We observed larger amounts of SP-immunoreactive and VIP-immunoreactive nerves in the mucosal layer of the appendix in patients with non-acute appendicitis than in controls and patients with acute appendicitis (mean % area SP-immunoreactive 0.0496 [SD 0.0113] non-acute, 0.0221 [0.0049] acute, 0.0229 [0.0068] controls). In addition, a close spatial relation between SP-immunoreactive and VIP-immunoreactive nerve fibres and lymphoid cells was detected in the outer zone of lymph follicles.

Interpretation: Neuroproliferation in the appendix, in association with an increase in neurotransmitters SP and VIP, may be involved in the pathophysiology of acute right abdominal pain in the absence of an acute inflammation of the appendix. Our data, together with increasing knowledge about the way in which the nervous system and immune cells interact, suggest that neuroimmune appendicitis is a distinct pathological entity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Pain / etiology*
  • Acute Disease
  • Adolescent
  • Adult
  • Aged
  • Appendectomy
  • Appendicitis / immunology*
  • Appendicitis / pathology
  • Appendix / immunology
  • Appendix / innervation*
  • Appendix / pathology
  • Diagnosis, Differential
  • Enteric Nervous System / immunology
  • Enteric Nervous System / pathology
  • Female
  • GAP-43 Protein / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / pathology
  • Male
  • Middle Aged
  • Neuronal Plasticity / physiology*
  • Prospective Studies
  • Substance P / metabolism*
  • Vasoactive Intestinal Peptide / metabolism*


  • GAP-43 Protein
  • Substance P
  • Vasoactive Intestinal Peptide