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Biomedical subjects

D E Nilssen

Publications and source records attributed to D E Nilssen.

18 recordsLinked to original sources
PubMed2004

Intestinal B cell hyperactivity in AIDS is controlled by highly active antiretroviral therapy.

BACKGROUND: It is well documented that highly active antiretroviral therapy (HAART) restores systemic immunity to human immunodeficiency virus (HIV) but the effect of this treatment on the mucosal immune system is less clear. AIMS: Because future preventive or therapeutic vaccines against HIV may be administered by the mucosal route, we wished to evaluate the effect of HAART on the activation level and homeostasis of the intestinal B cell system. PATIENTS AND METHODS: Duodenal biopsy specimens were collected consecutively from infection prone HIV positive adults (n = 31), mostly with advanced AIDS. In situ two colour immunofluorescence staining was performed to quantify mucosal immunoglobulin (Ig) class and subclass producing immunocytes (plasmablasts and plasma cells). RESULTS: HIV positive patients had, on average, duodenal proportions of IgA (74.6%), IgM (19.5%), and IgG (3.4%) immunocytes similar to median values recorded in 11 HIV seronegative healthy controls but the total immunocyte number per mucosal section length unit (500 microm) was significantly increased in patients (median 175 v 120 cells/unit; p<0.008), mainly comprised of IgA (p<0.02) and IgG1 (median 81.8% of total IgG; p<0.02) isotypes. Patients receiving a successful HAART regimen tended to normalise their IgG1 proportion and showed significantly lower total duodenal IgA immunocyte number than those receiving no or insufficient antiretroviral treatment (p<0.005). CONCLUSION: Our study demonstrated that advanced AIDS patients hyperactivate their intestinal B cell system. HAART could significantly reverse this perturbation, suggesting restored ability of the mucosal immune system to control intestinal infections.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Intestinal IgA- and IgM-producing cells are not decreased in marathon runners.

Alterations in duodenal immunoglobulin (Ig-)producing cells after excessive physical stress (marathon running) were studied by immunohistochemistry in 11 well-trained male adults, both shortly after running (race time, approximately 3.00 h) and later on after a "resting period" of 8-12 weeks with normal training (7-20 h/week). The ratios of IgA-, IgM- and IgG-producing cells were similar in the two biopsy specimens and virtually identical to those in eight normal duodenal controls (medians 77.6% IgA, 18.6% IgM, and 2.5% IgG). However, in the first sample the total number of positive cells per intestinal length unit was increased in five for IgA and in seven for IgM, while it was decreased in eight for IgG compared with the second biopsy. Also, the IgA cell number tended to be slightly increased immediately after the race (median 128 cells/unit) compared with that in normal controls (median 111 cells/unit); the same tendency was found for all Ig classes considered together. This apparent change was not explained by a thickening of the mucosa. Our study showed that marathon runners seem to maintain or even enhance their intestinal IgA and IgM-production, in contrast to the IgA decrease reported for other compartments such as salivary secretions and peripheral blood. The tendency to slightly increased intestinal IgA and IgM immunocyte populations in some runners might reflect a stress-induced hormonal influence on the homing of primed B cells to the mucosa, or perhaps an immune response to elevated influx of stimulatory luminal antigens.

Adolescent↗
PubMed1996

Intraepithelial gamma/delta T cells in duodenal mucosa are related to the immune state and survival time in AIDS.

The proportion of T-cell receptor gamma/delta+ cells and the CD4/CD8 ratio relative to all CD3+ intraepithelial lymphocytes (IEL) were determined by immunofluorescence in duodenal mucosa of late-stage (mostly CDC IVC1/D) subjects (n = 21) infected with human immunodeficiency virus type 1 (HIV-1). The gamma/delta fraction (median, 14.2%; range, 1.7 to 59.8%) was increased (P < 0.03) compared with that in HIV- controls (n = 11; median 2.8%; range, 0.3 to 38%). Also, the number of gamma/delta+ IEL per mucosal unit was increased (P < 0.05) in the HIV+ subjects (median, 11.1/U) compared with the controls (3.2/U). Approximately 100% of the gamma/delta+ IEL were CD8-, and most expressed the Vdelta1vJdelta1-encoded epitope (median, 90.9%). The total number of CD3+ IEL tended to be lower than in the controls (67.4 versus 72.9/U). Both the epithelium and the lamina propria contained mainly CD8+ T cells, the median ratios of CD4+ T cells being 1 and 7.6%, respectively. This result accorded with the reduced CD4 cell number in blood (median, 18 X 10(6)/liter). The HIV+ subjects had increased serum levels of neopterin and beta2-microglobulin (both P < 0.0001), probably reflecting immunostimulation. Serum neopterin and beta2-microglobulin were inversely related to duodenal gamma/delta IEL, particularly in the premortal group (r = -0.97 and r = -0.58, respectively). The increased gamma/delta IEL might reflect enhanced intestinal protection in late-phase HIV infection. Short survival expectancy (<7 months) was associated not only with high levels of neopterin and beta2-microglobulin but also with a reduced number of duodenal gamma/delta+ cells (P < 0.03).

Acquired Immunodeficiency Syndrome↗
PubMed1995

Reduced serum level of transforming growth factor-beta in patients with IgA deficiency.

Seventeen patients with IgA deficiency, 13 subjects with selective IgA deficiency and 4 with a combined IgA and IgG2 deficiency, were assessed for serum levels of cytokines relevant for B cell differentiation. Transforming growth factor (TGF)-beta was quantified by bioassay and interleukin (IL)-4, IL-6, and IL-7 by immunoassay. The serum levels of TGF-beta were significantly lower in patients with IgA deficiency than in healthy blood donors. Of the patients with IgA deficiency, 4 had detectable IL-4 levels while 4 of the others had detectable IL-6 levels in serum. IL-4 and IL-6 were not detected in the controls. Serum IL-7 levels were similar in patients and controls. A significant, negative correlation was found between serum TGF-beta and the number of circulating B lymphocytes in the patients with IgA deficiency. No association was found between serum cytokine levels and the occurrence of infections at the time of study. Since TGF-beta has been implicated in IgA isotype switching in man, and our study demonstrates an association between low serum TGF-beta levels and IgA deficiency, dysregulation of TGF-beta might be a contributing factor in the pathogenesis of IgA deficiency.

Adult↗
PubMed1993

Distribution and phenotypes of duodenal intraepithelial gamma/delta T cells in patients with various types of primary B-cell deficiency.

Expression of the gamma/delta T-cell receptor (TCR) on CD3+ intraepithelial lymphocytes (IEL) was studied in situ by two-color immunofluorescence on duodenal tissue sections from 34 infection-prone, adult patients with various types of primary hypogammaglobulinemia, classical Bruton's, Bruton-like or congenital, and common variable immunodeficiency. TCR gamma/delta+ IEL proportions (median 4.3%, range 0.3-43.3%) were within the range (0.3-38.3%) for histologically normal controls (n = 11), and there was no significant difference between the three patient categories. The total number of CD3+ IEL (mostly CD8+) per intestinal length unit was significantly higher (P < 0.004) in patients than in controls. In addition, TCR gamma/delta+ IEL per length unit, as well as TCR gamma/delta+ IEL proportions, were significantly increased (P < 0.008 and P < 0.05) in 14 patients with intestinal villous atrophy. Paired staining revealed that most (approximately 94%) TCR gamma/delta+ IEL in B-cell deficiency were CD8-, and a large fraction (approximately 67%) expressed the V delta 1/J delta 1-encoded epitope. No relationship was found between CD3+ or TCR gamma/delta+ IEL and the number of CD3+, CD4+, CD8+, and B lymphocytes or the CD4:CD8 ratio in peripheral blood. TCR gamma/delta+ IEL thus appeared to maintain a normal distribution in B-cell deficiency, except for being increased in patients with villous atrophy. Enhanced T-cell-mediated immunity, as possibly reflected by the numerical increase of CD3+ IEL, might compensate for a deficient mucosal B-cell system.

Adult↗
PubMed1993

Duodenal intraepithelial gamma/delta T cells and soluble CD8, neopterin, and beta 2-microglobulin in serum of IgA-deficient subjects with or without IgG subclass deficiency.

Expression of the gamma/delta T cell receptor (TCR) on CD3+ intraepithelial lymphocytes (IELs) was studied by two-colour immunofluorescence in duodenal tissue sections from healthy (n = 6) or infection-prone (n = 7) subjects with selective IgA deficiency (IgAD), and subjects (n = 4) with combined IgAD and IgG subclass deficiency. TCR gamma/delta+ IEL proportions in selective IgAD subjects (median 6.3%, range 1.0-41%) and in those with combined deficiency (median 4.5%, range 1.2-33%) were well within the range (0.3-38%) for histologically normal controls (n = 11), but the healthy IgAD subgroup tended to show raised TCR gamma/delta+ IEL proportions (median 13.6%) compared with the other two subgroups. Also the number of TCR gamma/delta+ IELs per intestinal length unit was relatively high (median 13.9/mm) in the healthy IgAD subjects, and significantly raised (P < 0.03) compared with controls (median 3.2/mm). Paired staining revealed that most TCR gamma/delta+ IELs in both selective IgAD (98%) and combined deficiency (99%) were CD8-, and a large fraction (median 84% and 63%, respectively) expressed the V delta 1/J delta 1-encoded epitope. The total number of CD3+ IELs (mostly CD8+) was similar to controls. IgAD subjects, and especially the healthy subgroup, had significantly increased serum concentrations of soluble CD8 (P < 0.0002), neopterin (P < 0.005), and beta 2-microglobulin (P < 0.007), which was similar to our previous observations in common variable immunodeficiency, and probably reflected stimulation of cell-mediated immunity. In addition, the increased TCR gamma/delta+ IELs might reflect a component of compensatory surface protection in the healthy IgAD subgroup.

Adolescent↗
PubMed1993

B-cell activation in duodenal mucosa after oral cholera vaccination in IgA deficient subjects with or without IgG subclass deficiency.

Alterations in duodenal Ig-producing cells induced by two oral cholera vaccinations were studied by two-colour immunofluorescence in mucosal tissue sections from adults with selective IgA deficiency (IgAD), either with (n = 7) or without (n = 9) frequent infections, infection-prone patients with combined IgAD and IgG subclass deficiency (IgGSD) (n = 7), and normal control subjects (n = 11). The proportion of IgG-producing cells prior to immunization tended to be lower in the symptomatic IgAD subjects than in the clinically healthy ones. In the first subgroup the absolute number of IgG cells per intestinal length unit was significantly increased after immunization (P < 0.04), and this tendency was also observed in the healthy IgAD subjects (6/9) and in those with combined deficiency (5/7). Very few IgAD subjects responded with an increase of IgM-producing cells. The normal controls responded variably in all major immunocyte classes, in the order IgA > IgG > IgM. Compared with these controls, the patients with combined IgAD and IgGSD showed significantly increased IgG1 (P < 0.01) and reduced IgG2 (P < 0.006) proportions, which was in accordance with their serum subclass levels. Our study showed that oral cholera vaccination preferentially activates intestinal IgG-producing cells in IgAD subjects. This result agreed with data recently obtained by ELISPOT in the same patients with regard to antibody-forming cells specific for cholera toxin. Both methods suggested that IgG rather than IgM antibodies are elicited as compensation for a lacking IgA response. However, our overall results showed that intestinal B-cell activation is quite variable after oral cholera vaccination. Although such vaccination might be of importance for enhancing mucosal immunity also in IgAD patients, a concurrent gut disease could possibly be aggravated by IgG-mediated mucosal immunopathology in the absence of anti-inflammatory IgA antibodies.

Adult↗
PubMed1992

Subclass composition and J-chain expression of the 'compensatory' gastrointestinal IgG cell population in selective IgA deficiency.

The subclass distribution of IgG-producing immunocytes was examined by two-colour immunohistochemistry in gastrointestinal mucosa of 14 patients with selective serum IgA deficiency providing the following biopsy material: gastric (n = 1); jejunal (n = 12); colonic (n = 1); and rectal (n = 2). All except two patients suffered from various infections, and coeliac disease was observed in six of them. Control reference data were based on biopsies from immunologically intact subjects, including histologically normal jejunal (n = 10) and large bowel (n = 10) mucosa and stomach mucosa with slight chronic gastritis (n = 8). The total mucosal population of immunoglobulin-producing cells per 500 microns gut length unit was only slightly decreased in IgA deficiency because of an increased number of IgG (30%) and especially IgM (71%) immunocytes. The IgG1 immunocyte proportion in the proximal gut (median 87%) was higher than that in the comparable controls (gastric 69%, jejunal 66%). A similar trend was seen in the distal gut (69%) compared with controls from the large bowel mucosa (55%). Conversely, IgG2 and IgG3 cell proportions were significantly decreased compared with the respective controls from the proximal gut. The same was true for IgG4, which also was significantly reduced in jejunal mucosa. Paired staining for cytoplasmic J chain and immunoglobulin isotype showed 71% positivity for jejunal IgG-producing cells in IgA deficiency, which was somewhat reduced compared with comparable controls (89%). J chain appeared to be preferentially expressed by IgG1 cells (75%), but was also found in IgG2 (70%), IgG3 (32%) and IgG4 cells (33%). IgM-producing cells showed a J-chain positivity (99%) in IgA deficiency similar to normal (100%). Our results suggested that the block in mucosal B cell differentiation to IgA expression in the proximal gut is mainly located immediately upstream to the CH alpha 1 gene, giving excessive terminal maturation of J-chain-positive IgG1 immunocytes.

Adolescent↗
PubMed1991

IgG subclass deficiency with or without IgA deficiency.

IgG subclass deficiency (IgGSD) is difficult to define since reference materials vary between laboratories and the clinically relevant cut off levels for the various subclasses are not well known. The diagnosis of IgGSD should be based on more than one determination since the levels vary, due to various factors such as infections, operations, etc. There is a relation between IgGSD and occurrence of frequent infections, but at the same time even total lack of a subclass can be seen in healthy individuals. Infections in the upper and lower respiratory tract predominate. Gm allotypes influence IgG subclass levels. Most IgGSD patients are homozygous in the Gm system. Immunocytes producing IgG3 in the nasal mucosa correlate with serum IgG3 levels, whereas rectal IgG1 producing cells relate to serum IgG1 levels. This may reflect differences in antigen and/or mitogen exposure at the two mucosal sites. IgG2SD is the predominant form of IgGSD among children, whereas after puberty IgG3SD is most common. At the same age period there is a switch in sex distribution from three boys/one girl to one male/three females. Various abnormalities in B and T lymphocyte numbers and function are often found. In a double blind crossover study of Ig prophylaxis over 2 years in 43 IgGSD adult patients a significant decrease in the number of days with infections was seen both in the whole group and among the IgG1 deficient. Days with bronchial constriction were also significantly decreased among the 22 patients who had asthma as well. Acute bronchitis became significantly less frequent in the IgG3 deficient patients during Ig prophylaxis. This was seen in those under the lower range of 0.41 g/liter of Oxelius' early normal material, although many recent reference materials suggest 0.14-0.15 g/liter of IgG3 as the cut off. In a group of 25 consecutive patients with IgGSD + IgA deficiency recurrent respiratory infections were the major problem and lung function impairment was found in 12, and bronchiectasies in 5. Still many individuals with this combined deficiency have been reported to be healthy, again illustrating our limited understanding of these conditions.

Disease↗
PubMed1991

Isotype distribution of mucosal IgG-producing cells in patients with various IgG subclass deficiencies.

The subclass distribution of IgG-producing immunocytes was examined by immunohistochemistry in nasal and rectal mucosa of infection-prone patients with untreated IgG subclass deficiencies. Biopsy specimens from the two sites were obtained in 18 clinically and serologically well-characterized adult subjects; only a nasal or rectal sample was available from nine similar patients. Chronic lung disease was common in the patient groups with selective serum IgG1 deficiency and combined IgG1 and IgG3 deficiency, whereas the other categories of patients had mainly upper airway and other mild infections. Serum IgG2 or IgG3 deficiency was usually expressed also at the cellular level in rectal mucosa, and the proportion of rectal IgG1 cells was significantly correlated with the IgG1 level (r = 0.90, P less than 0.001). Likewise, there tended to be a decreased expression of the actual subclass at the cellular level in nasal mucosa of patients with serum IgG1 or IgG2 deficiency. Conversely, the median nasal proportion of IgG3 cells was remarkably unaffected by a deficiency of this subclass in serum and rectal mucosa. Interestingly, these patients rather tended to have raised IgG3 and reduced IgG2 cell proportions in their nasal mucosa, although this apparent local IgG3 compensation was nevertheless strongly correlated with the serum IgG3 level (r = 0.87, P less than 0.002). These disparities may reflect different antigenic and mitogenic exposure of the two tissue sites; for example, a persistent protein bombardment of the nasal mucosa that could conceivably override locally a B cell maturation defect. The possible clinical consequences of such variable mucosal expression of IgG subclass deficiencies remain to be studied.

Adult↗
PubMed1991

Ontogeny of the mucosal immune system and IgA deficiency.

Studies of ontogenesis contribute to better understanding of regulatory events underlying the striking heterogeneity in B-cell differentiation pathways employed in the human mucosal immune system. This disparity is probably explained by exogenous environmental factors, although regional differences probably also exist in accessory cells and cytokines involved in local immune responses. IgA deficiency signifies a heterogeneous syndrome but is basically a manifestation of a defect in B-cell differentiation. The immaturity of the IgA system revealed in this disorder bears a striking resemblance to that seen in newborn infants. It may therefore be worthwhile to consider IgA deficiency in relation to the ontogeny of mucosal immunity.

Breast Feeding↗
PubMed1989

Short-chain fatty acids and other intestinal microflora-associated characteristics in faeces of patients with severe B-cell immunodeficiency.

The intestinal microflora of 18 patients with severe B-cell immunodeficiency was studied by determination of short-chain fatty acids (SCFAs) and other intestinal microflora-associated characteristics in the faeces. Glucose-hydrogen (H2) breath test was also performed. The results were within normal values in most of the patients, indicating no major pathologic changes in the intestinal bacterial microflora. These findings do not indicate any important role of the mucosa-associated B-cell system in the regulation of the composition and metabolic activity of the intestinal microflora.

Adolescent↗
PubMed1986

The many faces of Goodpasture's syndrome.

Four cases of antiglomerular basement membrane (antiGBM) antibody mediated disease with unusual features are presented. Lung involvement was absent in one patient whereas the other 3 had Goodpasture's syndrome. Recognition of the nature of the disease was delayed in all cases, due to occurrence during pregnancy in one case and due to the indolent course of the renal injury in the other 3 cases. The therapeutic approach to these variant forms of antiGBM antibody mediated disease is discussed.

Adult↗