Autoimmunity in Gastrointestinal Disease
Autoimmune enteropathy
Autoantibodies against gut enterocytes have been associated with:
Coeliac-like enteropathy (DQ2 positive), unresponsive to gluten-free diet, with villous atrophy.
Post stem cell transplantation.
Achalasia
Clinical features
Patients develop dysphagia for both liquids and solids.
Eventual massive dilatation of the oesophagus occurs.
Occurs in early to middle adult life.
Marked increase in the risk of subsequent oesophageal carcinoma.
Similar features occurs in the trypanosomal infection Chagas’ disease.
Immunopathology
Achalasia results from damage to the myenteric inhibitory neurons of the lower oesophagus.
Autoantibodies have been described that recognize the neurons of Auerbach’s plexus in the oesophageal wall in the idiopathic form of the disease; these are probably an epiphenomenon, and not disease-inducing.
25% of patients with achalasia have autoimmune thyroid disease.
Treatment
The lower oesophageal sphincter is dilated endoscopically or the muscle divided surgically (Heller’s myotomy).
Drugs to relax smooth muscle are also used (calcium-channel blockers and nitrates).
Botulinum toxin type A (Botox) injections may give temporary relief.
Eosinophilic gastroenteritis (including oesophagitis)
Presentation
Non-specific GI symptoms: abdominal pain, nausea, vomiting, weight loss, distension, reflux-like disease, dysphagia (oesophagus).
Associated with cholangitis, appendicitis, pancreatitis, giant duodenal ulcer, and eosinophilic infiltration of spleen.
↑incidence associated atopic disease and urticaria, and coeliac disease.
Any age/race/sex; higher incidence in later life. Incidence appears to be
ncreasing.
May be seasonal variation in presentation (higher in summer).
Immunopathology
Possible association with food allergy (tlgE to foods).
Association with hypereosinophilic syndromes (see Chapter 3).
→ IL-5, IL-13, IL-15, fibroblast growth factor 9, and eotaxin.
Diagnosis
Confirm by biopsy: >15 eosinophils/HPF.
Bowel wall may be thickened on scans.
Exclude other systemic and local diseases where bowel eosinophilia may be seen (Crohn’s disease, polyarteritis nodosa, Churg-Strauss syndrome, malignancy, parasites).
Treatment
Corticosteroids: may be used as swallowed steroid from inhaler for oesophagitis; oral budesonide for eosinophilic enteritis.
Trial of elimination diet if specific IgE to foods identified (rarely successful).
Sodium cromoglicate, ketotifen, and montelukast can be tried.
Omalizumab and anti-IL5 Mab have been tried in a small number of cases.
Crohn’s disease
Presentation
Crohn’s disease is an inflammatory disease affecting any part of the bowel, which may also be accompanied by disease distant from the bowel (skin, muscle).
Presents with diarrhoea and abdominal pain, or with evidence of the extra-GI complications.
Inflammation is transmural and granulomata are present.
There is superficial ulceration and crypt abscesses.
Skin lesions are common, and the deep penetrating ulceration frequently gives rise to fistulae.
Associated with seronegative arthritis, uveitis, and sclerosing cholangitis.
Malabsorption (especially of vitamin B12, as the terminal ileum is frequently affected) may occur.
Immunogenetics
Associated with DR5, DQ1 haplotype, or DRB*0301 allele.
Strong association with NOD-2 (CARD15) gene on chromosome 16 that senses bacterial peptidoglycan and regulates NF-κB expression.
Over 30 genes which contribute directly or indirectly have been identified including:
X-box binding protein 1 (XBP1)—a transcription factor regulating immune system genes in response to stress (endoplasmic reticulum and unfolded protein response)
autophagy-related protein 16-1 (ATG16L1).
Immunopathology
It has long been suspected that the disease is related to an infection, and current attention has focused on Mycobacterium paratuberculosis, which causes Jonne’s disease in cattle.
Measles has also been suggested as a possible trigger.
There is evidence of both a cell-mediated response and defective T-cell suppressor function.
Excess TH17 cells are critical to disease development.
Increased B-cell activity with immunoglobulin and complement deposition in damaged bowel.
Activated macrophages are present and mast-cell numbers are
ncreased.
Excessive inflammatory cytokines are present (TNFA).
Crohn’s disease should be considered to be a form of host-defence disease with impairment of the ability to handle intestinal bacteria correctly.
Diagnosis (see Box 7.1)
Crohn’s disease is associated with specific autoantibodies:
non-MPO P-ANCA (up to 25% of patients)
P-ANCA in Crohn’s disease is associated with colonic disease
anti-Saccharomyces cerevisiae antibodies (ASCA) (present in 60-70% of patients)
Other antibodies found in Crohn’s disease include:
anti-cardiolipin
anti-mycobacterial heat-shock protein
rheumatoid factors
anti-goblet cell
outer-membrane porin C (OMPC)—bacterial antigen
pancreatic autoantibodies
antibodies against tropomyosin isoform 5
antibodies against red cell membrane antigens that cross-react with Campylobacter—associated with haemolysis in Crohn’s disease
antibodies to a range of glycans (laminanbioside, chitobioside, mannobioside, laminarin, chitin).
none of these antibodies has realistic diagnostic value.
α1-acid glycoprotein (orosomucoid) was said to be more sensitive as an acute-phase marker for inflammatory bowel disease, but it really adds nothing to CRP.
Treatment
Treatment is with steroids, azathioprine, 6-mercaptopurine, methotrexate, ciclosporin, mycophenolate mofetil, and 5-aminosalicyclic acid derivatives.
Patients on immunosuppression need monitoring for side effects and prophylaxis against opportunist infections.
Thalidomide is also used for its anti-TNF effect.
Resistant disease is treated with anti-TNF agents: infliximab (5mg/kg), etanercept, adalimumab (Humira®), or certolizumab (Cimzia®) (pegylated Fab fragment of humanized anti-TNF).
Complications include development of TB, lymphoma, and autoimmune disease.
Natalizumab (Tysabr®), a humanized mAb against the A4 integrin, has been licensed in the USA for remission induction and maintenance of severe Crohn’s disease. A major risk is development of progressive multifocal leucoencephalopathy (PML).
Box 7.1 Testing for Crohn’s disease
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