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The gut as an immunological organ

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					          CLINICAL IMMUNOLOGY OF GASTRO-INTESTINAL DISEASE

The gut as an immunological organ

Mucosa - associated lymphoid tissue = MALT; Gut - associated lymphoid tissue = GALT (e.g.
tonsils, appendix and Peyer’s patches)

Lymphocytes in organised lymphoid aggregates: Peyer's patches
Lymphocytes in epithelium: intra-epithelial lymphocytes
Lymphocytes in lamina propria, derived from circulation

Peyer's patch micro-environment:

Uptake of antigen via M cells (specialised epithelial cells)
Macrophages and dendritic cells that activate T cells
T cells that regulate B cell isotype
B cells that make and secrete IgA monomers plus J (joining) peptide
IgA dimers formed in lamina propria and attach to secretory piece on epithelial cells which
allows them to be secreted into the lumen.

Intra-epithelial micro-environment:
Both CD8+ (75%) and gamma-deltas are found.

Recirculating pathway via mesenteric lymph nodes and blood stream with homing of IgA+ B
cells back to lamina propria and T blasts back to epithelium and lamina propria.
Repopulation of other mucosae, with some bias to site of origin.

Ag given to lactating females induces specific IgA responses in breast milk which can be
transferred to infant – this implies that immune protection can be transferred from one mucosal
site to another.

It has been suggested that systemic tolerance can follow oral administration of antigen, and this
may have therapeutic potential in auto-immunity.

Oral polio vaccine gives better protection: local IgA response blocks uptake? Or, is a local
protective immune response which is stimulated by a live and dividing attenuated virus bettre
that the killed virus used in the parenteral Salk injection?

Entero-hepatic circulation leads to Kupfer cell handling of antigen, or of complexes.

Circulating complexes of IgA and dietary Ags are often produced post-prandially.

Innate response: gastric acid, proteolytic enzymes, gut motility, physical barrier, macrophages

Adaptive response: secretory antibody, epithelial, Peyer's patch and lamina propria micro-
environments

Infection and immunity in the gastro-intestinal tract (see virology and microbiology teaching
material for detailed discussion):
1.   Viral
2.   Bacterial – e.g. bacillary dysentery, typhoid, infective colitis
3.   Parasitic – e.g. amoebiasis
4.   Opportunistic

Note that infection in the gastro-intestinal tract can result from immune deficiency, or can – in
severe cases – lead to it, e.g. severe malabsorption as cause of secondary immunodeficiency.



Immunopathology of the gut

1. Auto-immune gastritis / Immunopathology of pernicious anaemia

Presence of auto-antibodies to parietal cells, intrinsic factor, and other known auto-antigens.

Two forms of anti-intrinsic factor antibodies: act either by:
i)    blocking B12 binding to intrinsic factor – “binding antibody”
ii)   blocking absorption of B12 – intrinsic factor complex in terminal ileum – “blocking
      antibody”

Anti-parietal cell antibody: target antigen is gastric proton pump.

Antibodies found in gastric juice, but easier to measure serum levels.

Association with other auto-immune diseases.

Familial association.

The mainstay of treatment is rapid replacement of B12; clinical use of responses to steroids and
immunosuppressive drugs is limited, but does confirm auto-immune nature of condition.

Adverse reactions to food:

Immunological
Biochemical (incl. irritant, toxic, metabolic, pharmacological)
Psychological

Classified into three groups:

1. Food intolerance: abnormal reproducible reaction of unknown cause
2. Food allergy: immunologically mediated abnormal reaction – this is most important form as
i)     can test for this form of response
ii)    can treat with appropriate advice and diet
iii)   can be sufficiently severe as to be life threatening
3. Food idiosyncrasy: non-immunologically mediated abnormal reaction where cause is
recognisable

A role for adverse reactions to food has been suggested in the pathogenesis of a wide variety of
localised and classic symptoms - gastro-intestinal, rhinitis, asthma, urticaria, eczema
A role of adverse reactions to food in remote symptoms - migraine, hyperactivity, enuresis,
arthritis – has been suggested – there are many ideas about this, but little or no firm evidence –
the public is fascinated by this concept, and hence purveyors of alternative therapy find a ready
market in the field.

Elimination are crucial in diagnosis: e.g. nut allergy
Challenge diets: can be dangerous if not performed under strict supervision, e.g. in large allergy
centre, with access to immediate care should anaphylaxis ensue.
Type                           A                                  B
Disease associations           Auto-immune diseases               Age, previous surgery, peptic ulcer,
                                                                  malignancy
Possible cause                 Anti-parietal cell auto-antibody   Helicobacter pylori
Antral inflammation            Not present                        Present
Body inflammation              Present                            Not present
Antral gastric cell count      High                               Low
Serum gastrin                  High                               Low
Intrinsic factor               Low                                Normal
Auto-antibodies                Anti-parietal cell                 Anti-gastrin producing
                               Anti-intrinsic factor
                               (blocking or binding)



                              Parietal cell antibody                            Intrinsic factor antibody
Pernicious anaemia            Serum: 90% (IgG 65%, IgA 25%)                     Serum: blocking 70% (IgG)
                              Gastric juice: 70% (IgA)                          Gastric juice: blocking 85%
Auto-immune thyroid disease   20%                                               < 1%
Fe-deficient anaemia          25%                                               < 1%
IDDM                          20%                                               < 1%
Addison's                     20%                                               < 1%
Normals                       16%                                               < 1%
Immunopathology of coeliac disease

Presence of mucosal lesion: infiltration by lymphoid cells

Jejunal biopsy: loss of villi, increase in intra-epithelial T cells, inflammation and plasma cell
infiltrate in lamina propria.

Genetic factors: familial; -B8, -DR3, -DQ2

75% concordance in identical twins; 5-20% of 1st degree relatives; but only 0.1% -B8, -DR3, -
DQ2 + develop the disease

Alternative name: gluten-sensitive enteropathy

Antigen is gluten (found in wheat, barley and rye)

Active component is 7kD -gliadin polypeptide

Three hypothetical pathways: hypersensitivity to gluten (possible cross-reaction to adenovirus),
abnormal binding of gluten to lectin, defective enzymatic proteolysis.

Auto-antibodies present:

Auto-antibody against endomysium
Auto-antibody against tissue transglutaminase – highly specific and sensitive test

Associated auto-immune disease:

Endocrine, rheumatic and pulmonary; also dermatitis herpetiformis

Dermatitis herpetiformis: bullous skin eruption: 30% of patients also have coeliac disease and
same immunogenetic associations – granular deposits of IgA in the dermis – responds to gluten-
free diet.

Immunological complications:

hyposplenism, lymphoma, susceptibility to gastro-intestinal malignancy.

Investigations:

i. Tests to diagnose malabsorption:
e.g. xylose tolerance, faecal fat, immunoglobulins (IgG and IgA), Ca++, PO4-, alkaline
phosphatase, serum and rbc folates, serum albumin in severe late disease

ii. Tests to diagnose anaemia:
e.g. Hb, MCV, Fe-BC, serum B12, bone marrow, B12 absorption.

iii. Tests to diagnose cause of disease:
e.g. anti-gliadin, anti-endomysium, anti-tissue transglutaminase, jejunal biopsy.
iv. Tests to monitor disease associations:
e.g. HLA typing, auto-antibody screen.

v. Tests to monitor disease:
e.g. repeat jejunal biopsy, gluten challenge – to-day these are less frequently performed as it is
now possible to monitor by using non-invasive auto-antibody tests especially anti-gliadin and
ant-transglutaminase.


HIV and the gut

The main emphasis in discussion of HIV and the gut is on the effects of immunodeficiency, but
one also has to remember that the ano-rectal route is an important way that the disease is spread.

1. Oral pathology: infection: viral, bacterial and fungal; both pre-malignant and malignant
conditions.

2. Oesophageal disease: infection: viral (CMV, herpes, other viruses including HIV itself),
fungal (candida); idiopathic

3. Diarrhoea:
i.) "pathogen - free diarrhoea" - may be effect of HIV itself, and may be either effects on
epithelium or on T cell micro-environment.
ii) iatrogenic – due to HAART drugs
iii) protozoal: Microsporidia and Cryptosporidia
iv) bacterial: Mycobacterium avium intracellulare.
v) viral: CMV

4. Wasting

Combination of HIV infection, reduction of intake, anorexia, and opportunistic infection.

Lipodystrophy – fat loss from face and limbs – can be very disfiguring - in males loss of total
body weight, in females can be weight gain. Has been attributed to HAART (mitochondrial
toxicity) but can also be seen in those not on HAART so may be virus effect.

Difference between protozoal (treat cause, and will respond with improved diet) and
mycobacterial or CMV (treat cause, but often cachexia).

4. Abdominal pain

Arteritis and scelerosing cholangitis may complicate the disease

5. Neoplasia

Both Kaposi sarcoma and lymphoma can involve the gut

				
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posted:2/23/2010
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