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Autophagocytosis of the apical membrane in microvillus inclusion disease
K Reinshagen1, H Y Naim, K-P Zimmer
1Abteilung für Kinderchirurgie, Chirurgische Klinik der Ruprecht-Karls-Universität Heidelberg, D-69120 Heidelberg, Germany.
Background:
Microvillus inclusion disease (MID) is a disorder with the clinical signs of intractable diarrhoea in the newborn and infancy. The typical pathological features of the disease are well known whereas the pathophysiology is still unclear.
Aim:
This study was performed to define possible alterations of the cytoskeleton and exocytic as well as endocytic pathways within enterocytes in MID.
Patients:
Four patients with MID were studied. Three had a congenital onset of diarrhoea and one patient had a late onset form.
Methods:
Thin frozen sections of small bowel biopsies of patients were labelled by antibodies against the cytoskeleton and the brush border enzyme sucrase-isomaltase. The binding sites of the primary antibodies were visualised by immunogold particles in the electron microscope. Biopsies were labelled in organ culture to analyse the biosynthetic and endocytic pathways within the enterocytes.
Results:
Labelling with antibodies against actin and villin did not differ significantly in control and patient biopsies. Biosynthetic labelling revealed normal intracellular processing and transport of the brush border enzyme sucrase-isomaltase. Secretory granules in crypt epithelial cells were positive for sucrase-isomaltase, differing in its labelling density between patients. Patient biopsies showed microvillus inclusion bodies which endocytosed cationised ferritin within five minutes after uptake as well as ovalbumin after incubation for 10 minutes. These microvillus inclusion bodies correspond to early endosomes because they lack lysosome associated membrane proteins. Late endosomes and lysosomes containing sucrase-isomaltase did not reveal microvillus-like structures.
Conclusion:
Microvillus inclusion bodies in MID originate from autophagocytosis of the apical membrane of enterocytes with engulfing of microvilli.
Insights
Microvillus inclusion disease (MID) involves abnormal enterocyte apical membrane engulfment, forming microvillus inclusion bodies. This study reveals these bodies originate from autophagocytosis, clarifying MID pathophysiology.
Area of Science:
- Gastroenterology
- Cell Biology
- Pathophysiology
Background:
- Microvillus inclusion disease (MID) presents as intractable infant diarrhea, with known pathology but unclear pathophysiology.
- Understanding the cellular mechanisms underlying MID is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate potential alterations in the cytoskeleton and exocytic/endocytic pathways in enterocytes of MID patients.
- To elucidate the origin and nature of microvillus inclusion bodies observed in MID.
Main Methods:
- Analysis of small bowel biopsies from four MID patients (three congenital, one late-onset).
- Immunogold labeling of enterocyte cytoskeleton and sucrase-isomaltase.
- Organ culture of biopsies to study biosynthetic and endocytic pathways using tracers like cationized ferritin and ovalbumin.
Main Results:
- Cytoskeleton proteins (actin, villin) showed no significant differences between patients and controls.
- Biosynthetic processing of sucrase-isomaltase was normal, though its labeling density varied in secretory granules.
- Microvillus inclusion bodies were identified as early endosomes, actively endocytosing tracers, and lacked lysosome-associated membrane proteins.
Conclusions:
- Microvillus inclusion bodies in MID result from autophagocytosis of the enterocyte apical membrane, including microvilli.
- This finding provides a key insight into the pathophysiology of Microvillus Inclusion Disease.
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