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Biomedical subjects

E N Janoff

Publications and source records attributed to E N Janoff.

At least 55 records · Page 3Linked to original sources
PubMed1995

Response of recent human immunodeficiency virus seroconverters to the pneumococcal polysaccharide vaccine and Haemophilus influenzae type b conjugate vaccine.

Antibody responses in recent human immunodeficiency virus (HIV) seroconverters to 2 vaccines were studied. Twenty patients infected with HIV for < 18 months and 15 HIV-seronegative controls were vaccinated with the 23-valent pure polysaccharide pneumococcal vaccine and the Haemophilus influenzae type b (Hib) capsular polysaccharide diphtheria CRM197 protein toxoid conjugate vaccine in separate arms. Despite increased levels of total serum IgG, recent seroconverters and controls showed similar specific IgG responses for 6 of 7 antigens. Baseline levels were equivalent in both groups, as were peak levels of IgG at 1 month to conjugated polysaccharide (Hib), delayed-type hypersensitivity, and pneumococcal capsular serotypes 4, 6B, 12F, and 14. At 6 months, IgG levels were similar for 4 of 7 antigens. Antibody responses to pure pneumococcal capsular polysaccharides and to a protein recall antigen were most often similar among recent seroconverters and seronegative controls. Both total levels and fold-rises of IgG to the Hib conjugate were similar in the 2 groups. Immunization of HIV-infected patients soon after seroconversion rather than later appears to improve antibody responses.

Adult↗
PubMed1995

Antibody class and subclass responses to pneumococcal polysaccharides following immunization of human immunodeficiency virus-infected patients.

Antibodies of the IgM class and IgG2 and IgA2 subclasses are prominent in responses to pneumococcal polysaccharides (PPS) but may be decreased in human immunodeficiency virus (HIV)-infected patients, among whom invasive pneumococcal disease is common. After immunization of HIV-infected and -seronegative subjects with pneumococcal vaccine, the number of PPS-specific antibody-secreting cells (ASC) producing IgM was significantly lower among HIV-infected subjects, whereas PPS-specific IgG and IgA ASC were more comparable. The subclass distribution of PPS-specific IgG2-producing (approximately 80%) and IgA2-producing (approximately 50%) ASC and antibodies in serum were similar. However, before immunization, the proportions of PPS-specific IgG2 for both serotypes 8 and 14 in baseline sera from HIV-infected patients were significantly decreased compared with controls. Thus, the response to PPS among HIV-infected patients may be characterized by lower levels of specific IgG2 before immunization and prominent defects in IgM responses soon after stimulation.

Adult↗
PubMed1995

Impact of Streptococcus pneumoniae bacteremia and human immunodeficiency virus type 1 on oral mucosal immunity.

To determine whether defects in mucosal immunity were associated with invasive disease caused by a mucosal pathogen, Streptococcus pneumoniae, levels of salivary immunoglobulins and nonspecific immune factors were compared in subjects with human immunodeficiency virus type 1 (HIV-1) infection and in HIV-1-seronegative subjects with and without pneumococcal bacteremia. The IgA2 subclass may be of particular importance because S. pneumoniae produces IgA1 protease, which cleaves IgA1 but not IgA2. Levels (37-56 micrograms/mL) and proportions (11%-17%) of IgA2 were similar among groups. Serotype-specific capsular salivary IgA was present in a minority of patients with acute bacteremia. Levels of lactoferrin were increased with bacteremia. Neither selective mucosal IgA2 deficiency nor impaired nonspecific upper respiratory mucosal responses were associated with invasive pneumococcal disease during HIV-1 infection; thus, other defects in mucosal cellular responses and systemic immunity may predispose HIV-1-infected patients to invasive pneumococcal disease.

AIDS-Related Opportunistic Infections↗
PubMed1995

Modulation of human immunodeficiency virus type 1 infection of human monocytes by IgA.

The effect of IgA from human immunodeficiency virus type 1 (HIV-1)-infected patients on infection of primary human blood monocytes with the monocyte-tropic strain HIV-1Bal was evaluated in vitro. Preincubation of HIV-1Bal with purified serum IgA from 6 of 14 patients but from none of 5 seronegative subjects caused a > 50% increase in reverse transcriptase activity. This increase was inhibited by preincubation of monocytes with nonimmune IgA, suggesting a role for Fc alpha receptors. Results were independent of CD4 T cell number and clinical stage. The IgA-mediated enhancement extended to more biologically relevant human mononuclear cells isolated from the intestinal lamina propria. The ability of serum IgA to enhance HIV-1 infection may be relevant to infection of both circulating monocytes and mucosal macrophages. These studies suggest the need to characterize the complex contribution of IgA and the mucosal immune system in promoting and preventing primary HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Age, sex, and household exposure are associated with the acute measles-specific antibody-dependent cellular cytotoxicity antibody response.

To determine whether functional antibody responses correlate with factors associated with severe measles, measles-specific antibody-dependent cellular cytotoxicity (ADCC) and neutralizing antibodies were measured in 114 Filipino children with measles. Children > 24 months old were more likely to have ADCC antibody in acute sera than were those < or = 24 months (odds ratio = 3.6, 95% confidence interval = 1.7-7.8). This age-related difference in ADCC prevalence was most apparent between younger and older girls. Among children < or = 24 months, a higher prevalence of ADCC antibody was associated with male sex, absence of lymphopenia, and household exposure to measles. The presence of ADCC antibody was not associated with malnutrition or diarrhea. Neutralizing antibody titers were lower in children with lymphopenia but showed no relationship with the other variables. Thus, the ADCC antibody response is associated with some risk factors related to measles severity. Attenuation of this response may contribute to the severity of infection.

Acute Disease↗
PubMed1995

Selective neutralization of a bacterial enterotoxin by serum immunoglobulin A in response to mucosal disease.

One-third of convalescent-phase serum samples (6 of 18) from patients with Clostridium difficle-associated diarrhea demonstrated neutralization of the clostridial enterotoxin, toxin A. Although appreciable amounts of toxin A-specific immunoglobulin G (IgG) and IgA were present in these sera, the ability to neutralize the cytotoxic activity of toxin A on OTF9-63 cells in vitro was confined to the IgA fraction and the IgA1 subclass in serum samples from all six patients. In contrast to the patients with C. difficile diarrhea, this activity was present in both the IgA and IgG fractions in sera from two C. difficile-infected patients without diarrhea, one of whom presented with a splenic abscess. Sera and purified IgA which neutralized the cytotoxicity of toxin A on OTF9-63 cell cultures in vitro also neutralized the enterotoxicity of toxin A in rabbit ileal loops in vivo. This activity was not Fc dependent, since IgA retained neutralizing activity after pepsin digestion and F(ab')2 purification. The transition from nonneutralizing toxin A-specific IgA in the acute-phase sera to neutralizing specific IgA in the convalescent-phase sera was accompanied by a shift from a polymeric to a predominantly monomeric form of specific IgA. However, the neutralizing activity in convalescent-phase sera was present as both monomeric and polymeric IgA. Convalescent-phase sera from other patients with C. difficile diarrhea that failed to neutralize toxin A also failed to produce a predominantly monomeric-form specific IgA response. We conclude that serum IgA, not IgG, characteristically neutralizes toxin A in patients with C. difficile diarrhea who develop neutralizing systemic responses. This neutralization of an enteric bacterial toxin is a unique and selective role for serum IgA which provides a novel functional link between the systemic and mucosal immune systems.

Acute Disease↗
PubMed1995

Impaired natural immunity to pneumolysin during human immunodeficiency virus infection in the United States and Africa.

Human immunodeficiency virus (HIV) infection is associated with a significantly increased incidence of pneumococcal pneumonia and concomitant bacteremia. We hypothesized that the predisposition of HIV-infected patients to invasive pneumococcal infection may be related, in part, to an impaired immune response to the pneumococcal antigen pneumolysin (PLY) because PLY facilitates bacterial invasion. We measured serum anti-PLY antibodies in two separate populations of HIV-infected and HIV-seronegative controls, using both an enzyme-linked immunosorbent assay method and a functional assay of antibody inhibition of PLY-induced hemolysis and cytotoxicity. HIV-infected patients in the United States had significantly lower titers of anti-PLY antibodies by both methods than did seronegative control subjects. Moreover, HIV-infected patients in Kenya who later developed pneumococcal bacteremia also had significantly lower anti-PLY antibody levels at baseline compared with seronegative control subjects. We conclude that lower baseline levels of antibodies to PLY are associated with the higher incidence of bacteremic pneumococcal infections among HIV-infected patients.

AIDS-Related Opportunistic Infections↗
PubMed1995

Dual function of pneumolysin in the early pathogenesis of murine pneumococcal pneumonia.

Streptococcus pneumoniae is one of the most common etiologic agents of community-acquired pneumonia, particularly bacteremic pneumonia. Pneumolysin, a multifunctional cytotoxin, is a putative virulence factor for S. pneumoniae; however, a direct role for pneumolysin in the early pathogenesis of pneumococcal pneumonia has not been confirmed in vivo. We compared the growth of a pneumolysin-deficient (PLY[-]) type 2 S. pneumoniae strain with its isogenic wild-type strain (PLY[+]) after direct endotracheal instillation of bacteria into murine lungs. Compared with PLY(-) bacteria, infection with PLY(+) bacteria produced greater injury to the alveolar-capillary barrier, as assayed by albumin concentrations in alveolar lavage, and substantially greater numbers of PLY(+) bacteria were recovered in alveolar lavages and lung homogenates at 3 and 6 h after infection. The presence of pneumolysin also contributed to the development of bacteremia, which was detected at 3 h after intratracheal instillation of PLY(+) bacteria. The direct effects of pneumolysin on lung injury and on the ability of pneumococci to evade local lung defenses was confirmed by addition of purified recombinant pneumolysin to inocula of PLY(-) pneumococci, which promoted growth of PLY(-) bacteria in the lung to levels comparable to those seen with the PLY(+) strain. We further demonstrated the contributions of both the cytolytic and the complement-activating properties of pneumolysin on enhanced bacterial growth in murine lungs using genetically modified pneumolysin congeners and genetically complement-deficient mice. Thus, pneumolysin facilitates intraalveolar replication of pneumococci, penetration of bacteria from alveoli into the interstitium of the lung, and dissemination of pneumococci into the bloodstream during experimental pneumonia. Moreover, both the cytotoxic and the complement-activating activities of pneumolysin may contribute independently to the acute pulmonary injury and the high rates of bacteremia which characterize pneumococcal pneumonia.

Animals↗
PubMed1994

Antibodies to pneumococcal capsular polysaccharides in children with human immunodeficiency virus infection given polyvalent pneumococcal vaccine.

Antibody to 7 common pneumococcal capsular polysaccharides was measured in 11 children with human immunodeficiency virus (HIV) infection who had been previously vaccinated with 23-valent polysaccharide pneumococcal vaccine, 11 unvaccinated children with HIV infection, and 11 healthy subjects. No differences in capsule-specific IgG levels against serotypes 4, 6B, 8, 12F, 14, 19A, and 19F were observed among the vaccinees with HIV infection compared with unvaccinated children with HIV infection and age-matched control children.

Antibodies, Bacterial↗
PubMed1994

Clinical courses of seven survivors of Clostridium septicum infection and their immunologic responses to alpha toxin.

Clostridium septicum bacteremia typically portends a fulminant disease associated with high mortality. We describe the clinical courses of seven survivors of C. septicum infection and their antibody responses to the alpha toxin produced by C. septicum. Three patients had clinical syndromes ranging from uncomplicated bacteremia to early typhlitis, and three patients had syndromes ranging from abscess to myonecrosis and septic shock. In addition, an AIDS patient who developed septic shock and who had extensive gas in the retroperitoneal musculature did not undergo surgery but survived after receiving antimicrobial therapy and intensive supportive care. Both immunocompetent patients with myonecrosis had detectable IgG to alpha toxin by immunoblot analysis. IgG to alpha toxin was not detected in the four immunocompetent patients who had C. septicum bacteremia but who did not have myonecrosis or in the AIDS patient with myonecrosis. Therefore, humoral responses to alpha toxin during C. septicum infection may be related to the host's clinical syndrome and immune status.

Adult↗
PubMed1994

Intestinal mucosal immunoglobulins during human immunodeficiency virus type 1 infection.

In intestinal fluid samples from 39 human immunodeficiency virus type 1 (HIV-1)-infected patients, IgA and IgG levels were equivalent, whereas in 10 controls, IgA levels were significantly higher than those of IgG (P < .05). Intestinal IgA in patients contained predominantly monomeric IgA1, whereas IgA1 and IgA2 subclass levels in controls were nearly equivalent and primarily polymeric. The predominance of IgG and monomeric IgA1 in mucosal fluid samples from HIV-1-infected patients suggests exudation of serum immunoglobulins into the intestine. The decreased proportion of mucosal plasma cells producing IgA and IgA2 in the HIV-1-infected patients (P < .01) may also contribute to the abnormal intestinal immunoglobulin levels. Intestinal IgG reacted with most HIV-1 antigens, whereas specific IgA was present in only 10 of 17 patients and reacted with only envelope (gp120 and gp160) and, less often, core (p17 and p24) antigens. Aberrant mucosal antibody responses and decreased integrity of the mucosal barrier may contribute to the intestinal dysfunction and infections that characterize HIV-1 infection.

Diarrhea↗
PubMed1993

Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection.

Although invasive pneumococcal infections are common among men infected with human immunodeficiency virus (HIV), the prevalence of pharyngeal colonization with Streptococcus pneumoniae was not significantly different among HIV-infected patients (8 [14%] of 56) and HIV-seronegative men (9 [9%] of 99) attending a sexually transmitted disease clinic. Sixteen HIV-infected men (mean CD4+ T cell count, 132 +/- 37/microL) developed pneumococcal bacteremia, accounting for 13.6% of 117 total cases and 42% of 38 cases in men 16-55 years old. Serum killing activity, a measure of functional humoral response to S. pneumoniae, was lower in 4 (67%) of 6 acute sera and 6 (54%) of 11 convalescent sera from bacteremic HIV-infected patients when compared with baseline sera of 7 HIV-seronegative healthy subjects. These findings suggest that the high rates of pneumococcal bacteremia among HIV-infected patients may be associated with low numbers of CD4+ T cells and impaired humoral responses to S. pneumoniae rather than to increased exposure to the organism.

Adolescent↗
PubMed1993

Identification of hydrogen peroxide as a Streptococcus pneumoniae toxin for rat alveolar epithelial cells.

Streptococcus pneumoniae infections of the lung are associated with significant damage to the alveolar epithelium. Host phagocytes and pneumolysin, a cytolytic toxin of S. pneumoniae, are believed to contribute to this cellular damage, yet experiments in which these elements are absent demonstrate the presence of an additional soluble S. pneumoniae factor that is toxic to alveolar epithelium. We examined the effects of S. pneumoniae-associated alveolar epithelial cell injury by factors other than S. pneumoniae-derived pneumolysin or phagocyte products by exposing cultured rat type II alveolar epithelial cells (RAEC) to S. pneumoniae mutants that lacked pneumolysin activity. We found that mutant pneumolysin-deficient strains of S. pneumoniae produced injury to RAEC similar to that produced by the parent strains. A toxin of type 14 S. pneumoniae was distinguished from pneumolysin by physiochemical (i.e., molecular mass and heat stability) and functional (i.e., hemolytic activity and cytotoxic activity) properties and was identified as hydrogen peroxide. All S. pneumoniae strains tested produced hydrogen peroxide, and in many strains hydrogen peroxide production was comparable to that of activated neutrophils. We conclude that S. pneumoniae produces hydrogen peroxide in concentrations that are cytotoxic to RAEC in vitro and that alveolar epithelial damage due to hydrogen peroxide may be involved in the pathogenesis of host cellular injury in pneumococcal pneumonia.

Animals↗
PubMed1992

Pneumococcal disease during HIV infection. Epidemiologic, clinical, and immunologic perspectives.

OBJECTIVE: To characterize the epidemiology, clinical manifestations, and immunologic risk factors for infections with Streptococcus pneumoniae among persons infected with human immunodeficiency virus (HIV); and to delineate a practical approach for diagnosis, treatment, and prevention of these infections. DATA SOURCES: English-language articles from Index Medicus and their references as well as abstracts from conference proceedings that compared rates as well as clinical and microbiologic features of S. pneumoniae infections in HIV-infected patients. STUDY SELECTION: All human studies that included denominators, appropriate control groups, or sufficient clinical descriptions and animal studies with key immunologic observations were cited. DATA EXTRACTION: We compared epidemiologic and clinical responses to pneumococcal disease in HIV-infected patients and control subjects and correlated clinical and experimental data on immunologic defects associated with HIV infection with those on regulation of pneumococcal infections. DATA SYNTHESIS: Among patients with HIV infection, the incidence of invasive pneumococcal disease is high, bacteremia is a common complication of pneumonia, and relapses occur frequently. However, the clinical presentation, response to therapy, and serotypes isolated are similar to those in persons without HIV infection, and mortality is similar or lower. Specific local and systemic defects in host defense, particularly humoral immunity, may contribute to the high incidence of invasive pneumococcal disease. CONCLUSIONS: Streptococcus pneumoniae is the leading cause of invasive bacterial respiratory disease in adults and children with HIV infection. Prompt diagnosis and antimicrobial therapy are associated with a favorable clinical outcome. Characterizing the specific immunologic defects associated with invasive pneumococcal disease in HIV-infected patients may facilitate development of successful, cost-effective strategies for prophylaxis.

HIV Infections↗
PubMed1992

NIH conference. Gastrointestinal infections in AIDS.

As the largest lymphoid organ in the body, the gastrointestinal tract is a potential reservoir for human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), and it is an important site for HIV-induced immunodeficiency. The resulting defects in cellular and humoral defense mechanisms predispose the gastrointestinal tract to a spectrum of viral, fungal, bacterial, and protozoan pathogens that cause relentless morbidity and, in some cases, death. With a thorough diagnostic evaluation, physicians can identify one or more of these pathogens in a majority of patients with AIDS who have gastrointestinal symptoms. The identification of enteric pathogens in patients with AIDS is important because an increasing array of therapeutic regimens is becoming available to treat many of these infections.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Systemic and mucosal antibody responses to toxin A in patients infected with Clostridium difficile.

The systemic and mucosal humoral response to toxin A, the primary virulence factor of Clostridium difficile, was measured in sera and intestinal secretions from 21 patients with C. difficile diarrhea, 9 asymptomatic C. difficile fecal excretors, and 10 noncolonized control subjects. Toxin A-specific IgG was higher in convalescent sera of the patients with diarrhea (mean +/- SE, 990 +/- 260 ng/mL) than in acute sera (620 +/- 150 ng/mL), in sera from asymptomatic excretors (410 +/- 140 ng/mL), or control subjects (320 +/- 50 ng/mL; P < .05 convalescent vs. control). The pattern of toxin A-specific serum IgA and intestinal secretory IgA levels was similar to that of serum IgG in these groups. Neutralization of toxin A was demonstrated in 5 of 14 convalescent sera but only 1 of 13 acute sera (P = .04). However, the presence of neutralizing activity was independent of the subsequent clinical response. Therefore, most patients convalescent from C. difficile diarrhea demonstrate systemic and mucosal antibodies to toxin A, but these antibodies following natural infection do not appear to alter the clinical course of C. difficile infection.

Adult↗
PubMed1992

Toxicity of pneumolysin to pulmonary endothelial cells in vitro.

Pneumococcal pneumonia and bacteremia are associated with appreciable mortality, most of which occurs very early in the course of infection. An initial step in the pathogenesis of pneumococcal pneumonia may include disruption of the pulmonary endothelial barrier with subsequent alveolar hemorrhage. We sought to determine whether soluble factors from Streptococcus pneumoniae can directly injure pulmonary endothelial cells in vitro and to identify pneumococcal toxins that may be involved in endothelial cell injury. Suspensions of S. pneumoniae (10(8) organisms per ml) caused significant injury to cultured bovine pulmonary artery endothelial cells in a time-dependent manner. The degree of endothelial cell cytotoxicity differed among S. pneumoniae strains; among the strains tested, a type 14 strain was the most cytotoxic and a type 3 strain was the least cytotoxic. During autolysis, type 14 S. pneumoniae released a soluble endothelial cell cytotoxin that was distinct from S. pneumoniae capsular and cell wall polysaccharides. The soluble cytotoxin was further characterized as a thiol-activated, heat-sensitive protein that coeluted with purified pneumolysin during gel filtration. The identity of the S. pneumoniae endothelial cell cytotoxin as pneumolysin was further supported by the ability of purified pneumolysin and the inability of S. pneumoniae mutants which lack pneumolysin to injure endothelial cells, as well as by the inhibition of the soluble S. pneumoniae cytotoxin by a neutralizing antibody to pneumolysin. Pneumolysin appears to be the major S. pneumoniae soluble cytotoxin for pulmonary endothelial cells in vitro and may be an important factor in the pathogenesis of alveolar hemorrhages in S. pneumoniae infections.

Animals↗