A UK national audit of hereditary and acquired angioedema.

Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life-threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.

Absence of toxicity of oats in patients with dermatitis herpetiformis.

BACKGROUND: People with gluten sensitivity should avoid foods containing wheat, rye, and barley, but there has been debate about whether they should avoid oats. Although patients with celiac disease have recently been shown to tolerate oats, less is known about the effects of oats on patients with dermatitis herpetiformis. METHODS: We studied seven men and three women (mean age, 58 years) with biopsy-confirmed dermatitis herpetiformis. They had followed a strict gluten-free diet for a mean of 15.8 years, which controlled their rash and enteropathy. The patients added oats that were not contaminated with gluten to their diets for 12 weeks (mean [+/-SD] daily intake, 62.5+/-10.8 g). RESULTS: None of the patients had any adverse effects. Serologic tests for antigliadin, antireticulin, and antiendomysial antibodies were negative before oats were introduced into the diet and after they were discontinued. Villous architecture remained normal: the mean (+/-SE) ratio of the height of villi to the depth of crypts was 3.59+/-0.11 before the diet and 3.71+/-0.09 afterward (normal, 3 to 5), and the mean enterocyte heights were 31.36+/-0.58 microm and 31.75+/-44 microm, respectively (normal range, 29 to 34). Duodenal intraepithelial lymphocyte counts all remained within normal limits (mean, 13.8+/-1.03 per 100 enterocytes before the diet and 14.2+/-1.2 per 100 enterocytes afterward; normal range, 10 to 30). Dermal IgA showed no significant changes. CONCLUSIONS: Patients with dermatitis herpetiformis can include moderate amounts of oats in their gluten-free diets without deleterious effects to the skin or intestine.

Active psoriasis and profound CD4+ lymphocytopenia.

We report the case of a patient with a long-standing history of widespread chronic plaque psoriasis, who was recently found to have a profound CD4+ lymphocytopenia. He is human immunodeficiency virus (HIV) negative. His psoriasis remains active and widespread, and he has had 60 cutaneous malignancies, including many squamous cell carcinomas, excised over the last 10 years. In the past he has had numerous cutaneous viral warts. Despite a low peripheral blood CD4+ T-cell count, similar numbers of activated T cells, identified by double labelling for CD4 and HLA-DR antigens, were found in the epidermis of our patient as other individuals with psoriasis. Thus, there appear to be sufficient activated CD4+ T cells in our patient's psoriatic plaques to maintain the psoriatic process.

Relationship of in vitro phagocytosis of serotype 14 Streptococcus pneumoniae to specific class and IgG subclass antibody levels in healthy adults.

The role of specific IgG2 antibody in the protection against serious infection with Streptococcus pneumoniae is unclear. We therefore decided to investigate the relationship between serum antibody levels and opsonization and phagocytosis of this microorganism. We have measured serum IgM, IgA and IgG subclass antibody specific for pneumococcal capsular polysaccharide and in vitro phagocytosis of serotype 14 pneumococcus by polymorphs, in healthy adults before and after immunization with Pneumovax II. IgM and IgG2 were the predominant anti-pneumococcal antibodies seen, IgA and IgG1 being present at low titre. No significant relationship of phagocytosis with specific IgM and IgA antibodies was found. However, both specific IgG1 and IgG2 antibodies in post-immunization sera correlated significantly with phagocytosis of the pneumococcus in the presence of complement (r = 0.57, P = 0.029 and r = 0.59, P = 0.022 respectively). After heat-inactivation, the remaining opsonic activity of sera correlated only with levels of specific IgG2 antibody (r = 0.61, P = 0.0006). Whereas phagocytosis supported by specific IgG1 and IgG2 antibody to serotype 14 pneumococcus after immunization is mediated by complement activation, IgG2-specific antibody in high titre may also be able to function by complement-independent interaction with Fc gamma receptors on polymorphs.

Class- and subclass-specific pneumococcal antibody levels and response to immunization after bone marrow transplantation.

Immunoglobulin class- and subclass-specific antibodies to a polyvalent pneumococcal capsular polysaccharide vaccine (Pneumovax II) were measured before and after immunization in children, 1 year or more after bone marrow transplantation for a variety of genetic disorders. The median titres of specific IgG, IgG1 and IgG2 pneumococcal antibodies fell significantly (P less than 0.05) from pre-transplantation levels. The levels of pneumococcal antibodies in the patients before immunization were markedly lower than those in control children of comparable age, for antibodies of IgM, IgG, IgG1 and IgG2 classes (P = less than 0.001 in each case). Apart from IgG2 antibodies, the median response to immunization with Pneumovax II was not significantly different from the controls (P greater than 0.05). However, because of the lower pre-immunization levels, the patients did not achieve a high post-immunization-specific antibody titre in any immunoglobulin class or subclass, when compared with normal children. Neither the pre-immunization specific antibody levels nor the response to immunization were affected by splenectomy or the presence of chronic graft-versus-host disease. Immunization of the donor before bone marrow harvest did not influence the level of specific antibody 1 year or more after transplantation. No significant correlation was found between the total serum IgG2, the patients' age at the time of assessment, or time after transplantation, and the IgG2-specific antibody response. The lack of specific antibodies and the poor IgG2 response to pneumococcal antigens may contribute towards the occurrence of infection with Streptococcus pneumoniae in the late post-transplantation period.

Autoantibodies after bone marrow transplantation in children with genetic disorders: relation to chronic graft-versus-host disease.

The occurrence of autoantibodies and their relation to chronic graft-versus-host disease (GVHD) have been studied in children, 100 days or more following allogenic bone marrow transplantation (BMT), mainly performed for a variety of genetic disorder. Seventeen of 40 patients had autoantibodies to thyroid microsomes, compared with none of 46 control children of similar age (p less than 0.001). The presence of these antibodies was strongly associated with chronic GVHD (14 of 20 patients), p = 0.001. IgG antibodies to the cytoplasm of squamous epithelial cells were demonstrated in 15 of 36 children following transplantation (p less than 0.001), none being found in 46 normal children. The incidence and titre of these antibodies were significantly higher in patients with chronic GVHD (p = 0.041 and p = 0.019 respectively). Despite there being a significant number of patients with antibodies to nuclei, smooth muscle and gastric parietal cells, these autoantibodies were not related to the presence of chronic GVHD. Although the mechanism of production is not known, antibodies to thyroid antigens and the cytoplasm of squamous epithelial cells may be useful markers for GVHD.

Specific IgG subclass antibody levels and phagocytosis of serotype 14 pneumococcus following immunization.

Complement and specific antibody directed against capsular polysaccharide are necessary for efficient phagocytosis of pneumococci. In normal adults, specific antibody to pneumococci is predominantly of the IgG2 subclass. However, the role of IgG2 in bacterial clearance is debatable. We therefore decided to investigate the relationship between specific IgG subclass antibody levels and phagocytosis of serotype 14 pneumococcus, before and after immunization with a pneumococcal capsular polysaccharide vaccine. Specific IgG subclass antibody was measured by an ELISA technique and the effect of serum on phagocytosis of radiolabelled pneumococci by normal polymorphs was determined. We found that in the presence of complement, phagocytosis correlated significantly with both specific IgG1 and IgG2 antibody titres (r = 0.547, P = 0.002 and r = 0.464, P = 0.009, respectively). However, in decomplemented sera, the correlation with IgG1 antibody was lost, whereas that with IgG2 antibody was strengthened (r = 0.641, P = less than 0.001). The possibility that IgG2 binds to receptors on polymorphs should be considered.

Early-onset neonatal pneumococcal sepsis in siblings.

The case of a woman who in two successive pregnancies produced premature infants affected by early-onset Streptococcus pneumoniae type 8 sepsis is described. Low maternal levels of pneumococcal IgG antibodies were demonstrated after the second delivery, and vaccination with 'Pneumovax' produced a rise in antibody levels. Attention is drawn to the similarity between early-onset pneumococcal neonatal sepsis and group B streptococcal sepsis. Mothers of infants affected by early-onset pneumococcal sepsis who have low pneumococcal antibody levels run the risk of subsequent babies being similarly affected and vaccination should be considered to prevent recurrence.

Newly produced virgin B cells migrate to secondary lymphoid organs but their capacity to enter follicles is restricted.

The migration of recirculating B cells was compared with that of newly produced virgin B cells following passive cell transfer between congenic strains of rats differing in their kappa immunoglobulin light chain (kappa) allotype. The number and location of donor B cells in the secondary lymphoid organs was determined at intervals following transfer by immunohistology using monoclonal antibodies specific for rat kappa allotypes. Recirculating B cells were obtained from thoracic duct lymph while bone marrow from rats depleted of recirculating cells was used as a source of newly produced virgin B cells. B cells from both sources gained immediate access to extrafollicular areas of secondary lymphoid organs rich in interdigitating cells and T cells. However, in lymph nodes extrafollicular B cells were found adjacent to lymphatics and not in the central paracortex. By 8 h after transfer most B cells from thoracic duct lymph were found in follicles. However, the capacity of the bone marrow B cells to enter follicles was very limited. These results are interpreted in relation to previous observations concerning (a) the timing of virgin B cell recruitment into T cell-dependent antibody responses, and (b) the role of B cells in antigen presentation.

Distinct short-lived and long-lived antibody-producing cell populations.

This report analyzes the life span of Ig-containing cells (IgCC) in different sites of antibody production. The experimental approach was based upon the observations that most IgCC are derived from proliferating precursors while IgCC themselves are mainly nondividing end cells. Rats were given a continuous infusion of [3H] thymidine via an osmotic pump inserted in the peritoneal cavity. At intervals of 1, 3, 5 or 10 days after starting infusions, tissues were taken and analyzed by a combination of immunohistology and autoradiography to identify the proportions of IgCC which had gone through S phase of the cell cycle during the period of infusion. After 3 days infusion the median and (range) percent-labeled IgCC in the medullary cords of mesenteric and cervical lymph nodes and the red pulp of the spleen were, respectively, 88 (81-90), 75 (66-77) and 88 (82-93). Conversely that for IgCC in bone marrow was only 13 (11-17) and that in the lamina propria of the jejunum 47 (33-68). The rate of increase in labeling of bone marrow IgCC with length of infusion was approximately linear. Extrapolation of this slope suggests that bone marrow IgCC have a life span in excess of 3 weeks. The slopes of increase in IgCC labeled with time for lymph nodes and spleen were clearly biphasic suggesting that while most IgCC in these tissues have a life span of less than 3 days, there is also a minor population of long-lived IgCC. The lamina propria appears to have approximately equal proportions of long and short-lived IgCC. The life span of IgCC, with the exception of IgMCC, appears to be a feature of the site of antibody production rather than the Ig class produced. Almost all IgM-containing cells were found to be short lived.

Relation of intra-splenic migration of marginal zone B cells to antigen localization on follicular dendritic cells.

Injection of heat-killed Escherichia coli into rats results in massive loss of IgM + ve, IgD - ve B cells from the marginal zones of their spleen within 4 hr. This is matched by a concomitant increase of cells with this phenotype in the splenic follicles. The marginal zone remains depleted and the follicles distended for about 16 hr, but the histological picture returns to normal within 24 hr. Surface marker analysis of blood and spleen B lymphocyte populations throughout the course of the migration suggest that there is intrasplenic migration of IgM + ve cells from marginal zone to follicles rather than via the circulation. Factors inhibiting localization of immune complex on follicular dendritic cells were assessed for their influence on marginal-zone B cell migration. Immune complex, injected 5 hr post-endotoxin administration localized poorly on follicular dendritic cells. While C3 depletion, by cobra venom, has no effect on marginal-zone B cell migration induced by endotoxin, it completely inhibits transport of heat-aggregated human gammaglobulin to follicular dendritic cells.

Suppressor cells assayed by numerical and functional tests in chronic renal failure.

Suppressor cells were assayed by numerical and functional tests in adults on chronic hemodialysis. Peripheral blood mononuclears (PBM) were classified as total T-cells by E-rosettes and by the monoclonal antibody OKT3, as T-cell subsets by OKT4 (inducer/helper T-cells) and OKT8 (cytotoxic/suppressor T-cells) and as B-cells by the presence of surface immunoglobulin. The suppressive effect of PBM pretreated with either Concanavalin A (Con A), sodium periodate, or serum rich in immune complexes, on normal homologous phytohemagglutinin (PHA) lymphocyte transformation, was determined. Usual tests of T-cell function were not done. T lymphopenia was due to significant diminution (P less than 0.002) in numbers of OKT4+ cells in patients (516 +/- 44 cells/mm3, mean +/- sem) as compared to controls (906 +/- 96 cells/mm3). The number of OKT8+ cells in patients was not different from normal although their percentage (45 +/- 4%) was slightly higher than controls (36 +/- 5%) (P less than 0.10). Suppressor activity using only a suboptimal dose of Con A (5 micrograms/ml), was significantly lower (P less than 0.002) in uremic patients (36 +/- 12%) than in controls (67 +/- 7%). An important finding was that no significant correlations were detected between the numerical and functional assays of suppression used or between any of these immunological tests and biochemical parameters studied. The implications of these results for immunoparesis in uremia are discussed with particular reference to the discordance between marker and functional assays of suppressor cells.