William O. Dobbins

Antibiotic treatment and relapse in Whipple's disease

Abstract Reports of clinical relapse occurring after apparently successful antibiotic treatment of Whipples disease prompted this review of long-term follow-up of treated patients. Follow-up of at least 1 yr after completion of treatment or 2 yr after diagnosis was obtained on 88 patients with documented Whipples disease by a review of the medical literature, correspondence with the authors as needed, and questionnaires mailed to academic gastroenterology programs in the United States. Relapse was defined on the basis of morphology (preferably) or clinically, or both. Thirty-one patients relapsed, 6 of whom relapsed twice. Fifty-seven patients did not relapse. The mean time to relapse was 4.2 yr. The mean follow-up period of patients who did not relapse was 8.2 yr. The type and number of relapses were as follows: clinical, 16; central nervous system, 13; arthralgia, 5; gastrointestinal, 1; and cardiac, 2. The clinical, arthralgia, and gastrointestinal relapses were evenly distributed between early relapses (occurring 2 yr after diagnosis). All cardiac and central nervous system relapses were late. Twenty-one of 49 patients treated with tetracycline alone relapsed. Two relapses were reported in 15 patients treated with penicillin and streptomycin followed by tetracycline. Three relapses developed in 8 patients treated with penicillin alone. Five of the 16 patients treated with other regimens relapsed. Nine of the 13 patients with central nervous system relapse had been initially treated with tetracycline, 2 were treated with penicillin, and 2 were treated with combinations of antibiotics. Results of treatment of central nervous system relapse were poor in 10 of the 11 patients for whom details were available. Results of treatment of non-central-nervous-system relapse were excellent in 19 of 20 patients. It is concluded that tetracycline alone, or penicillin alone, is not adequate initial therapy for Whipples disease and that central nervous system relapse is resistant to antibiotic therapy. The authors recommend parenteral penicillin and streptomycin followed by 1 yr of oral trimethoprim-sulfamethoxazole therapy or oral trimethoprim-sulfamethoxazole alone for 1 yr as initial therapy for Whipples disease. Relapse should be defined by demonstration of recurrence of bacilli whenever possible.

Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease

Using monoclonal antibodies to T and B lymphocytes, to natural killer cells, and to HLA-DR antigen, we characterized the lymphocyte population within the epithelial and lamina propria regions in control intestine and colon, and in grossly involved and in grossly uninvolved intestine and colon of patients with active inflammatory bowel disease. There were significantly more intraepithelial T cells in control ileum than in control colon. In comparison to control, there was a heterogeneity of alterations in intraepithelial and lamina propria T lymphocyte subsets (T11+, T8+, T4+) in inflammatory bowel disease. B lymphocytes were not detected within the lamina propria, except when found in and adjacent to lymphoid aggregates. Leu 7+ cells were uncommon in the lamina propria of control ileum and colon and in diseased tissues. The majority of intraepithelial lymphocytes did not express HLA-DR. Epithelial cells of control colon did not express HLA-DR while epithelial cells of control ileal tissues and of diseased colonic and ileal specimens expressed HLA-DR antigen. Only small numbers of lamina propria T cells expressed HLA-DR in both control and disease tissues. There was intense expression of HLA-DR by monocytes and modest expression of HLA-DR by capillary and lymphatic endothelial cells. The induction of HLA-DR expression by diseased colonic epithelium and the observation that lymphatic endothelium expresses HLA-DR are new observations, and we established that Leu 7+ cells are present in very small numbers in both normal and diseased intestine and colon.

Electron microscopy of the intestine and rectum in acquired immunodeficiency syndrome.

To provide a better understanding of the morphologic changes that take place in the intestine and colon in acquired immunodeficiency syndrome (AIDS), electron microscopy was performed on intestinal or colonic biopsy specimens obtained from 6 patients with AIDS and from 2 patients with AIDS-related lymphadenopathy syndrome. Cryptosporidia were attached to the plasma membrane of epithelial cells in 2 patients and were noninvasive. An invasive protozoan organism identified as Microsporidia was found in 1 patient. Evidence for epithelial cell injury was limited. Unusually prominent secretory granules in colonic epithelial cells (a morphologic counterpart of secretion) was found in 2 patients. Tubuloreticular structures were observed in 7 patients. The structures were found in endothelial cells, lymphocytes, monocytes, intraepithelial lymphocytes, and free in the capillary lumen. Tube- and ring-shaped forms were observed in 2 patients, prominent intraepithelial mast cells in 4 patients, rectal spirochetosis in 1 patient, and pseudomembranous colitis in 1 patient with intestinal and systemic shigellosis. Vesicular rosettes, retroviruses, other viruses, and Mycobacterium avium-intracellulare were not observed. These observations expand our knowledge of morphologic changes in the colonic and intestinal mucosa in patients with AIDS. Tubuloreticular structures are so prominent, in contrast to our previous electron-microscopic observations in other disease and normal states of the intestine and colon, that their finding (though clearly nonspecific) may be a clue to the diagnosis of AIDS in an otherwise equivocal situation.

Heterogeneity of Cytochrome P450IIIA Expression in Rat Gut Epithelia

The P450IIIA (CYP3A) cytochromes are a major family of enzymes that play an important role in the metabolism of many medications, including cyclosporine A, as well as some dietary xenobiotics, including aflatoxin B1. The purpose of the studies was to detect, localize, and characterize P450IIIA enzymes present throughout the digestive tract. To this end, P450IIIA-specific antibodies were used to examine gut epithelial microsomes and histological tissue sections obtained from the digestive tract of both male and female rats. P450IIIA-related proteins were detected in epithelia throughout the gut; however, the specific proteins expressed appeared to differ among digestive organs and between male and female rats. RNA obtained from the gut epithelia was also analyzed using P450IIIA-specific synthetic oligonucleotides as probes on Northern blots and as primers for the polymerase chain reaction. P450IIIA1, which is a dexamethasone inducible enzyme in liver, was also found to be induced by dexamethasone treatment in epithelia from stomach and jejunum, but not from colon or esophagus. It was concluded that P450IIIA enzymes are present in mature epithelia throughout the gastrointestinal tract. However, expression of the P450IIIA enzymes is influenced by anatomic location and gender.

Immunoelectron microscopic localization of HLA-DR antigen in control small intestine and colon and in inflammatory bowel disease

We have elucidated the distribution of I2 (HLA-DR) antigen in control and inflammatory bowel disease specimens, using immunoelectron microscopic methods. Control small intestinal epithelium and inflammatory bowel disease epithelium expressed I2 antigen, while control colonic epithelium did not. I2 expression by enterocytes was more frequent on the lateral and basal surface than on the microvillus surface. Two of three M cells in control ileum expressed I2 antigen. I2-positive intraepithelial lymphocytes were rarely detected in both control and disease specimens. I2-positive lamina propria lymphocytes were significantly increased in inflammatory bowel disease, while I2-positive lamina propria lymphocytes were virtually absent in control specimens. I2-positive mononuclear cells in the intestinal lamina propria were largely macrophages and monocytes in both control and inflammatory bowel disease specimens. I2-positive mononuclear cells resembling dendritic cells were not detected in control or disease specimens. Furthermore, there were no significant morphological differences in I2-positive or-negative macrophages and monocytes in control and disease specimens. The expression of I2 antigen on Schwann cells was detected more frequently in disease specimens than in control specimens. Capillary endothelia of both control and disease specimens expressed I2 antigen. We demonstrate that I2 expression is present on surface membranes of both immune and nonimmune cells of the intestine and colon and show that this expression is more prominent in inflammatory bowel disease than in control intestine and colon. Further studies are required to determine whether this finding is meaningful in terms of antigen presentation and whether this apparent “immune activation” is involved in the pathogenesis of inflammatory bowel disease.

Is there an immune deficit in Whipple's disease?

There is controversy as to the role of immune deficiency, if any, in Whipples disease. This report summarizes published data in regard to immune function in this disease. Thirty-two publications during the past ten years offer varying amounts of immunological data in 61 patients — 50 males, 6 females, and 5 patients in whom the sex was not reported. There is no evidence for humoral immune deficiency in these patients. Secretory immunoglobulins are within normal limits. Intestinal mucosal plasma cells are decreased before treatment, but are normal after treatment. There are no abnormal deposits of complement or immunoglobulins within the intestinal mucosa. There is no evidence for autoantibody production. These patients invariably have lymphocytopenia prior to treatment and have a decreased percentage of T cells both before and after treatment. There is decreased responsiveness of lymphocytes to the mitogens PHA and Con A, before and after treatment. The cutaneous response to antigens is clearly diminished before treatment, improves somewhat after treatment, but is still significantly less than that seen in normal controls. There may be an increased association with HLA B27, which suggests that an abnormality in the cellular immune system promotes susceptibility to the Whipple bacillus.There is controversy as to the role of immune deficiency, if any, in Whipples disease. This report summarizes published data in regard to immune function in this disease. Thirty-two publications during the past ten years offer varying amounts of immunological data in 61 patients — 50 males, 6 females, and 5 patients in whom the sex was not reported. There is no evidence for humoral immune deficiency in these patients. Secretory immunoglobulins are within normal limits. Intestinal mucosal plasma cells are decreased before treatment, but are normal after treatment. There are no abnormal deposits of complement or immunoglobulins within the intestinal mucosa. There is no evidence for autoantibody production. These patients invariably have lymphocytopenia prior to treatment and have a decreased percentage of T cells both before and after treatment. There is decreased responsiveness of lymphocytes to the mitogens PHA and Con A, before and after treatment. The cutaneous response to antigens is clearly diminished before treatment, improves somewhat after treatment, but is still significantly less than that seen in normal controls. There may be an increased association with HLA B27, which suggests that an abnormality in the cellular immune system promotes susceptibility to the Whipple bacillus.

Reversal of dementia associated with Whipple's disease by trimethoprim-sulfamethoxazole, drugs that penetrate the blood-brain barrier.

A previously healthy 67-yr-old man presented with progressive dementia over an 11-mo period. Evaluation revealed evidence of malabsorption. Jejunal biopsy established the diagnosis of Whipples disease. No other etiology for the patients dementia was uncovered. Treatment with trimethoprim-sulfamethoxazole resulted in rapid elimination of Whipples bacilli from the jejunum and complete reversal of the patients dementia over a 6-mo period. Significant levels of trimethoprim and sulfamethoxazole were easily quantitated in the cerebrospinal fluid during therapy. There is increasing recognition of progressive neurologic disease in patients with Whipples disease who were treated with tetracycline. The reversal of presumed central nervous system disease in this case suggests that drugs that penetrate the blood-brain barrier might be preferable for the initial treatment of Whipples disease.

Familial visceral neuropathy with neuronal intranuclear inclusions: diagnosis by rectal biopsy.

A family with a visceral neuropathy manifested as chronic idiopathic intestinal pseudo-obstruction is reported. Diagnoses were made histologically by simple rectal biopsy. Discrete eosinophilic intranuclear inclusions, diagnostic of a disease known as neuronal intranuclear inclusion disease, were found in the submucosal ganglion cells. Abnormalities of the autonomic nervous system were identified by pupillary examination and electroretinography. In this family, three of four siblings were affected by the disease, which is apparently transmitted from the paternal side. This pedigree was unique for several reasons: (a) diagnosis in multiple members of two generations indicates that this familial visceral neuropathy was expressed in an autosomal dominant manner, (b) central autonomic nervous system abnormalities were detected by eye examination, and (c) the definitive pathological diagnosis was established antemortem by rectal biopsy in all cases.

Electron and Light Microscopic Identification of the Mast Cell of the Gastrointestinal Tract

Light and electron microscopic features of mast cells of the human gastrointestinal tract are described. The submucosal mast cell is easily identified in periodic acid- Schiff stained sections routinely prepared in this laboratory. Their unique cytoplasmic granules, microvilli, rounded nuclei with densely packed chromatin, sparse endoplasmic reticulum, and prominent cytoplasmic filaments afford unequivocal electron microscopic identification. Mast cells in the lamina propria and submucosa are frequent enough to make easy their detection at electron microscopy. The presence of mast cells within the intestinal epithelium is demonstrated for the first time using electron microscopy. The relationship of some of the structural aspects of the cells as they may relate to function is discussed.

A quantitative morphological analysis of ethanol effect upon rat liver.

Ethanol ingestion causes morphological changes in the livers of man and animals. This report describes a quantitative morphometric analysis of ethanol effects upon rat liver and a comparison with some biochemical determinations. Twenty-four rats were divided into three pair-fed groups: chow and 25% ethanol in drinking water; chow and an amount of sucrose isocaloric to the ethanol; and 25% ethanol in water and chow supplemented with 2% choline. After 35 days, a portion of liver was prepared for electron microscopy by standard techniques. Liver was analyzed for total phospholipid, triglyceride, lecithin, nitroreductase activity, and aniline hydroxylase activity. Twenty-five electron micrographs were obtained randomly from each specimen. Micrographs were analyzed by the lineal analysis method for cell and nuclear dimensions, and fractional volume of cytoplasmic components including mitochondria, peroxisomes, lysosomes, lipid bodies, and glycogen. Surface area of the mitochondrial envelope and the endoplasmic reticulum membrane and the approximate volume of mitochondria and peroxisomes were determined. Subjective analysis of electron micrographs failed to distinguish clearly the controls from the ethanol-treated rats. However, lineal analysis with statistical evaluation showed increased hepatic cell size (P