This case report describes a 30-year-old woman with a 4-week history of bloody diarrhea and abdominal pain who was diagnosed with Crohn's disease. Examination revealed tenderness and anal skin tags. Sigmoidoscopy showed red, granular mucosa with contact bleeding. Tests found low hemoglobin and elevated CRP. A rectal biopsy showed ulceration, crypt abscesses, and non-caseating granulomas diagnostic of Crohn's. She was initially treated with steroids and antibiotics with some improvement but later developed worsening symptoms. Treatment with the monoclonal antibody infliximab provided periods of remission for several months at a time.

1. Clinical Immunology
(spring 2015)
A case report
By
Ihab Muhammad Mahmoud
Medical Research Institute -
Alexandria

2. Case profile
• A 30 year-old woman was admitted a 4-week
history of increasing bloody diarrhoea and
abdominal pain.
• She has lost 3kg in wt.
• She smoked 25 cigarettes a day

3. Examination
• Not clinically anaemic.
• Temperature of 37.8°C.
• She was tender over the right fossa.
• A number of hypertrophic tender anal skin
tags which thought were haemorrhoids.

4. Examination
• Sigmoidoscopy to 15 cm
showed:
– Red, granular mucosa
with mucopus and
contact bleeding.

5. Laboratory investigations
• Low haemoglobin (108 g/l)
• Raised C-reactive protein (CRP) (67 mg/l)
• Normal white cell count.
• Urea and electrolyte, serum vitamin B12 , folate,
iorn , ferritin and iorn- binding capacity were
normal.
• Total serum proteins were 54 g/l (NR 62-82).
• Serum albumin of 29 g/l (NR 35-50).

6. Laboratory investigations
• ANCA (antibodies to neutophil cytoplasmic
antigens were not detected.
• Faecal examination and culture revealed no
ova or Campylobacter.
• Colistridium difficile toxin was absent from the
stool

7. Rectal biopsy
• showed a small area of ulceration of the
surface epithilium with considered mucopus.
• Many crypt abscesses were present.
• The lamina propria contained a heavy
infiltrate of lymphocytes, plasma cells and
macrophages.

8. Rectal biopsy
• Several non-caseating
granulomas were
present in the muscular
layer. (Crohn’s)

9. Barium examination
• Small bowel barium
examination showed
extensive areas of
fissuring ulceration
interspresed with areas
of apparently normal
mucosa-skip lesions.

10. Corticosteroid treatment
• Treated with corticosteroid and 3 month course of
metronidazole with symptomatic improvement.
• She was strongly advised to stop smoking but refused
to heed this advice.
• Over the next 2 years, her symptoms worsened , with
an anal fistula ,persistent diarrhoea and colicky lower
abdominal pain despite prednisolone 15 mg per day.
• She was weaned off prednisolone and started on
budesonide, but then developed spondyloarthropathy
of the left hip, both knees and her left wrist.

11. TNF Monoclonal antibody
• Because of her limited response to steroids, she was
given an intravenous infusion of a monoclonal antibody
to TNF – infliximab.
• Clinically, she improved and her bowels were open two
or three times each day and without nocturnal
diarrhoea. This remission lasted nearly 3 months
before her profuse diarrhoea and abdominal pain
returned.
• She has now had four infusions of infliximab, each
inducing symptomatic improvement of several months’
duration.
• She still smokes.

12. Inflammatory
Bowel
Disease
Crohn’s
Disease
Ulcerative
colitis

13. Inflammatory bowel disease
• Ulcerative colitis and Crohn’s disease are chronic
inflammatory disorders of the gastrointestinal tract, with a
tendency to remit and relapse.
• Ulcerative colitis affects only the colon, and is confined to
the mucosal layer.
• Crohn’s disease, on the other hand, may affect any part of
the gastrointestinal tract from mouth to anus, although the
ileocaecal region is most frequently involved. It can affect
the colon alone and then must be distinguished from
ulcerative colitis and other diseases causing segmental
colitis, the latter being associated with long-term use of
non-steroidal anti-inflammatory drugs.

15. Immunological test
• Acute phase protein:
– Monitoring disease activity and response to
treatment (specially in Crohn’s disease).
– C-reactive protein (CRP).
– Orosomucoid.
• Immunofluorescence:
– DNase-sensitive antineutrophil cytoplasmic
antibodies, with perinuclear highlighting that is
distinct from: pANCA & cANCA
– 60% of ulcerative colic patients and 20% of Crohn’s
patients.

16. Histology
• Histologically Crohn’s disease and ulcerative
colitis are distinct though the common finding is
inflammation – as suggested in the term
‘inflammatory bowel disease’.
• Transmural inflammation in Crohn’s disease
involves lymphocytes, plasma cells and
eosinophils, and there is granuloma formation .
The mucosa in ulcerative colitis is infiltrated with
neutrophils as well as plasma cells and osinophils.

17. Granulomatous inflammation in Crohn's disease.
• A section of bowel wall
from a patient with Crohn's
disease.
• The arrow marks a giant cell
granuloma.
• There is a dense infiltrate of
lymphocytes throughout
the bowel submucosa.

18. Pathogenesis of Crohn’s disease
Genetic
susceptability
Gut microflora
Immune-
mediated tissue
imjury

19. Intestinal Immune system
• The innate and adaptive immune systems normally
cooperate to limit inflammatory responses to intestinal
bacteria through a combination of mechanisms:
– a mucus layer produced by goblet cells;
– tight junctions between the intestinal epithelial cells;
– antimicrobial peptides released from epithelial cells and Paneth
cells;
– induction of Treg cells that inhibit effector CD4 T-cell
development and promote the production of lgA antibodies that
are transported into the intestinal lumen, where they inhibit
translocation of intestinal bacteria.

20. Intestinal Immune system

21. Genetic factor
• Genetic factors contribute to the pathogenesis of Crohn’s
disease and have a more dominant role than in
ulcerative colitis since siblings of patients have a much
higher risk of developing Crohn’s disease than the
general population.
• Crohn's disease susceptibility genes of innate immunity
include NOD2 and the autophagy genes ATG 16L 1 and
IRGM.
• A major susceptibility gene that affects adaptive immune
cells is IL23R, which is expressed by TH17 cells.

22. Genetic susceptability
• In individuals with impaired homeostatic
mechanisms, dysregulated TH1- and TH17
-cell responses to the intestinal microbiota
can result, → generating disease-causing
chronic inflammation.

23. Crohn's disease
Crohn's disease results from a
breakdown of the normal homeostatic
mechanisms that limit inflammatory
responses to the gut microbiota.

25. Pathogenesis of Crohn’s disease
• Crohn’s disease is a polygenic disorder and mutations in the
nitric oxide dismutase (NOD)2 genes on chromosome 16.
• NOD2 is a cytosolic receptor for pathogenic components of
gut bacteria.
• Defective NOD2 makes its bearer susceptible to Crohn’s
disease, but this is only one of several genes linked to this
condition
• The variants of NOD2 associated with Crohn’s disease give a
reduced response to LPS in dendritic cells, so reduced
signalling through this innate immune pathway and
activation of other inflammatory pathways, particularly in
neutrophils.

26. Pathogenesis of Crohn’s disease

27. Pathogenesis of Crohn’s disease
• Crohn’s disease is driven by activated TH1 cells secreting IL-12,
TNF-α and IFN-γ with an important role for TH17 cells, in
response to commensal bacterial exposure.
• In response to these cytokines, the main mediators of tissue
damage are matrix metalloproteinases generated by
neutrophils.
• T-effector cells also show increased resistance to apoptosis,
and with reduced Tregs, this allows the inflammatory process
to continue.

28. Ulcerative colitis
• Ulcerative colitis results from environmental
factors triggering a loss of tolerance to intestinal
flora in genetically susceptible individuals.
• Environmental factors: cigarette smoking
• early appendectomy seem to be protective, while
lack of breastfeeding and treatment with NSAIDs
increase the risk of developing ulcerative colitis
responds to treatment with metronidazole

29. Ulcerative colitis
• failure of goblet cell function or
differentiation:
– ↓mucus layer in the ascending colon thinner
– ↓ mature goblet cells
– ↓mucin synthesis

30. Pathogenesis of Crohn’s disease

31. Manegment
• Monoclonal antibodies to TNF-α such as
infliximab is proven to be safe and effective
treatment for severe, resistant or fistulating
Crohn’s disease
– About 50–65% of patients (responders)
– 20–30% patients go into (remission),
– infliximab to be used as maintenance therapy in
some cases.

33. Manegment
• Experimental antibodies to α4-integrins can block
T-lymphocyte migration into inflammatory foci,
• Anti-IL-12 and anti-IL-6 receptor induces
apoptosis.
• Alteration of the gut microbial environment by
probiotics
• cessation of smoking
• no innovative treatments have been developed to
treat ulcerative colitis specifically, though
infliximab is useful in a small proportion of
patients.

34. Monitoring (remission & relapses)
• Colonoscopy (invasive)
• Serum CRP
• faecal calprotectin
– calcium and zinc binding protein
– 60% of total proteins in the cytosol fraction in
neutrophil granulocytes (antimicrobial peptide
AMP)) →indicates an excess of neutrophils in the
bowel.

35. THANK YOU
Referance
Helen chapel Essential of clinical immunology 2014