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Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function.

Patients with multiple myeloma are generally immunodeficient, with pronounced depression in primary antibody responses. We have attempted to delineate the reasons for the humoral immunodeficiency by analyzing the specificity repertoire of the surface immunoglobulin (Ig)-positive B cells in patients with multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS), in comparison with normal donors. B lymphocytes from 26 patients with multiple myeloma, 12 patients with MGUS, and 8 normal donors were transformed with Epstein-Barr virus (EBV) and cultured at limiting dilution for clonal analysis. The Ig secreted by each clone was analyzed for class and anti-tetanus toxoid (TT) specificity to determine the frequencies of IgM, IgG, anti-TT IgM, and anti-TT IgG antibody-secreting clones. Our objective was to establish whether the inability to mount humoral responses to common environmental pathogens was due to a lack of specific B cells or to inhibition of B-cell function. Our results indicate that the quantitative B-cell deficiency in patients was due to a nonrandom loss of selected sets of B cells. Although most patients had a reduced aggregate number of B cells, the number of TT-specific B cells was normal. There was, on average, a threefold increase in the proportion of the B-cell specificity repertoire devoted to recognition of TT. Forty-four percent of the patients with MGUS were also affected. In addition, the TT-specific B cells in multiple myeloma patients were severely compromised in their ability to secrete antibody or to differentiate to antibody-secreting cells in vivo. This arrest in differentiation appears to be extrinsic to the B cells, as they were fully able to secrete anti-TT antibody after transformation and culture in vitro. We postulate the existence of an autoimmune inhibitory network mediating the arrest in B-cell differentiation and the humoral immune deficiency.

B-Lymphocytes↗

Effects of subchronic treatment with O,O,S-trimethyl phosphorothioate on cellular and humoral immune response systems.

The effect of a 14-day treatment with low doses of O,O,S-Trimethyl phosphorothioate (OOS-TMP), an impurity in technical malathion, on the generation of cell-mediated and humoral immune responses was examined in female C57B1/6 mice. At a dose of 0.5 mg/kg/day OOS-TMP, the generation of antibody-secreting cells to sheep red blood cells (SRBC), the production of interleukin 2 (IL-2), and proliferative responses to the mitogens concanavalin A (Con A) and lipopolysaccharide (LPS) were elevated. In contrast, the cytotoxic T-lymphocyte (CTL) response to alloantigen was unchanged. At 5.0 mg/kg/day OOS-TMP, both the CTL and specific antibody response were unchanged, but all other immune parameters examined were elevated. Data from cell separation and reconstitution experiments indicated that both macrophages and B cells were affected by this treatment regime. These data suggest that long-term exposure to low amounts of OOS-TMP may enhance the ability of an animal to generate an immune response.

Administration, Oral↗

[HBs-antigenemia and the state of cellular and humoral immunity in children with chronic viral hepatitis B].

In chronic virus hepatitis B the causative virus replicates for a long time as manifested by HBsAg persistence. Examinations of 92 sick children revealed changes in cellular and humoral immunity indices. The content of T-lymphocytes (determined according to Bach et al.) was reduced to 31.5 +/- 1.4% in the exacerbation stage (the normal content 50.8 +/- 1.3%), the percentage of O-cells increased, while the number of B-cells according to Mendes et al. did not change significantly. The inhibition of adhesion of A-cells (Halliday et al.--A. F. Blyuger) and "immune" plaque formation (according to A. F. Blyuger) in the presence of HBsAg were also increased maximally in the exacerbation stage. HBs-antigenemia was found to occur most frequently in the exacerbation stage. The content of immunoglobulin G was reduced. An increase in the number of tissue lymphocytes and their blast forms (in the "skin window" sample by Rebuck) was demonstrated. The authors assume that the long-term persistence of HBs-Ag and, consequently, the maintenance of the pathologic process activity are due to a defficiency of cellular immunity factors. The prospects of enhancing cellular immunity in virus hepatitis B in children are discussed.

Adolescent↗

An in vitro assessment of cellular and humoral immune function in pulmonary tuberculosis: correction of defective neutrophil motility by ascorbate, levamisole, metoprolol and propranolol.

Fifty-six tuberculosis patients and twenty-eight control subjects were evaluated in a comprehensive investigation of cellular and humoral immune function in pulmonary TB. The patient group showed significantly higher levels of secretory IgA and serum IgG, IgA and IgM than did the control group but 7% of patients displayed a selective secretory IgA deficiency. Levels of alpha-1-antitrypsin were also significantly higher in the patient group. There were no significant differences in levels of total haemolytic complement, C'3 and C'4. In moderate to moderately advanced TB patients there were no significant differences in T and B cell numbers nor in mitogen-induced lymphocyte transformation and lymphokine production, when compared with the control group. The range of PPD-induced lymphocyte transformation and lymphokine production levels encountered was similar in both groups although certain patients did not respond to the PPD antigen. Neutrophils from TB patients showed increased random motility in vitro but eight out of ten patients showed impaired directed motility (chemotaxis). Phagocytic and anti-microbial functions were normal in the patient group. The neutrophil chemotactic defect was reversible and could be corrected in vitro when the patients' cells were treated with sodium and calcium ascorbate, levamisole, metoprolol and propranolol.

Antibody Formation↗

Enhancement of humoral immunity by interleukin-12.

We have found that IL-12 treatment of mice leads to long-lasting enhancement in production of most antibody isotypes in conventional B-cell responses. Initial recruitment of new B-cell clones into the response is mediated by IFN-gamma, but subsequent enhancement of Ig secretion appears to be IFN-gamma-independent. We have further found that activated B cells can directly bind IL-12. Taken together, our results suggest a two-step model for the role of IL-12 in enhancement of humoral immunity. Initially, IL-12 induces production of IFN-gamma from Th1 and NK cells. Enough cytokine can be produced from either cell type to then mediate gamma 2a heavy chain isotype switching as well as temporary suppression of IgG1 production. IL-12 further stimulates post-switched cells, including cells producing IgG1, to secrete greatly increased amounts of antibody. This step is not mediated by IFN-gamma but might be due to direct IL-12 binding to activated B lymphocytes. Depletion of B1 cells by IL-12 may further enhance antibody responsiveness since B1 cells are known to competitively inhibit Ig secretion by conventional B cells. The end result is that IL-12 causes a generalized upregulation in production of all antibodies and therefore acts as a strong adjuvant for humoral as well as cellular immunity.

Adjuvants, Immunologic↗

Complement receptor type two (CR2,CR21): a target for influencing the humoral immune response and antigen-trapping.

Cellular receptors for complement C3 fragments deposited on antigens are important bricks in the wall defending against microbial pathogens. The part of complement receptor type 2 (CR2; CD21) deals with enhancing humoral immune responses and with long-term trapping of C3d-coated antigen by follicular dendritic cells. CR2 is also pivotal for Epstein-Barr virus (EBV) infection. Here, the current understanding, how CR2 interacts with its ligands C3d, EBV, and CD23 is summarized. The potential to target CR2 for clinical therapy or immunization purposes are discussed.

Adjuvants, Immunologic↗

Modification of humoral immune response in chickens following treatment with carrageenan.

Carrageenan treatment of chickens resulted in splenomegaly and enlargement of bursa but had no effect on the thymus. The dose and route of administration had a profound effect on humoral immune response to Brucella abortus and sheep red blood cells. Antibody response to B. abortus was either unaffected or significantly enhanced, whereas response to red blood cells was severely suppressed. Furthermore, delineation of the class of antibody response affected by the treatment, using 2-mercaptoethanol, suggested that there was a selective inhibition of IgG response to the T dependent antigen.

Animals↗

Cytomegalovirus vaccine: persistence of humoral immunity following immunization of renal transplant candidates.

A randomized, placebo-controlled, double-blind trial of Towne live, attenuated cytomegalovirus (CMV) vaccine in renal transplant candidates underway since January 1979 has enabled us to assess the durability of humoral immunity after immunization. Among 53 seronegative subjects, Towne vaccine elicited a geometric mean indirect immunofluorescent (IF) antibody titre of 72.3, but titres in patients either not transplanted or given kidneys from seronegative donors declined substantially by one year postimmunization. Vaccine boosted the geometric mean IF antibody titre in 21 seropositive untransplanted subjects from 66.5 pre-immunization to 91.0 approximately three months later. Seventeen seronegative subjects given a seropositive kidney and 27 subjects seropositive before immunization experienced a sharp boost in geometric mean antibody titre posttransplant signifying reactivation of their own CMV strain or acquisition of virus from the donor kidney. These data indicate that Towne vaccine is immunogenic in renal transplant candidates but does not completely prevent posttransplant infections.

Antibodies, Viral↗

The effect of nonspecific immunostimulation of pregnant mares with 1,3/1,6 glucan and levamisole on the immunoglobulins levels in colostrum, selected indices of nonspecific cellular and humoral immunity in foals in neonatal and postnatal period.

The objectives of the studies were to evaluate the effect of levamisole and 1,3/1,6 glucan applied in pregnant mares on parameters of non-specific cellular and humoral immunity of foals. Eighteen mares in three experimental groups (six animals in each) and their progeny were examined. Multiparous mares, crossbreed of Polish, full-blood and Hannover lines (400-500 kg), 4-9 years old, originated from four different farms. They were kept under identical zoohygienic and nutritional conditions. The animals were randomly chosen in experimental groups. None of mares had been previously vaccinated. In group I, levamisole was injected three times at 7-day intervals at a dose of 2.5 mg/kg of body weight. Group II was injected at the same periods of time and manner with 1,3/1,6 glucan at a dose of 0.19 mg/kg of body weight, whereas mares in group III served as controls. Injection of the immunostimulators started in mares 4-6 weeks before expected parturition. Blood was taken from foals before the first dose of colostrum, then 18 and 36 h after the first dose of colostrum and on Days 7, 14, 21, 28, 35, 42, 49 and 56 of life. The parameters determined in blood were reduction of NBT by PMNs, phagocytic activity, phagocytic index, test of intracellular killing and in blood sera were total protein, gamma-globulin fraction, lysozyme activity, level of IgG, IgG(T), IgM and IgA. In the first dose of colostrum taken just after parturition, specific gravity, total protein, gamma-globulin complex, lysozyme activity, level of IgG, IgG(T), IgM, IgA were determined. Colostrum of mares immunostimulated with levamisole or 1,3/1,6 glucan were characterized by a high content of IgG and IgG(T) compared to the colostrum of nonstimulated mares. The level of immunity was higher in foals from dams immunostimulated with levamisole or 1,3/1,6 glucan. Clinical examinations in neonatal and postnatal period did not show any abnormalities in these foals.

Adjuvants, Immunologic↗

The humoral immune response to the kinetoplastid membrane protein-11 in patients with American leishmaniasis and Chagas disease: prevalence of IgG subclasses and mapping of epitopes.

The kinetoplastid membrane protein-11 (KMP-11) is a major target of the humoral immune response during Leishmania-infections. The majority of sera from visceral leishmaniasis, mucocutaneous leishmaniasis and even some cutaneous leishmaniasis patients contain detectable IgG antibodies against KMP-11. We also provide evidence that this protein may act as a potent antigen in T. cruzi infections, since most Chagas sera show immunological cross-reactivity. Therefore, KMP-11 cannot be used as a specific diagnostical tool for the serodiagnosis of leishmaniasis in those regions where both, Leishmania and T. cruzi infections overlap geographically. When analyzing the subclass specificity of the antibody response to KMP-11 we observed the following order of reactivity: IgG1 > > IgG3 > IgG2 > IgG4, which is similiar to that seen in crude parasite extract. The mapping of antigenic determinants by using synthetic 20-mer peptides revealed the existence of predominantly conformational epitopes in leishmaniasis, while 50% of sera from Chagas patients reacted with a particular KMP-11 peptide. These results therefore suggest the presence of disease-specific B-cell epitopes.

Amino Acid Sequence↗

Immunoblot detection of class-specific humoral immune response to outer membrane proteins isolated from Salmonella typhi in humans with typhoid fever.

The studies reported here were undertaken to assess the ability of the outer membrane proteins (OMPs) of Salmonella typhi to induce a humoral immune response in humans with typhoid fever. OMPs were isolated with the nonionic detergent Triton X-100 and were found to be contaminated with approximately 4% lipopolysaccharide. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis patterns showed protein bands with molecular size ranges from 17 to 70 kilodaltons; the major groups of proteins were those that correspond to the porins and OmpA of gram-negative bacteria. Rabbit antiserum to OMPs or to S. typhi recognized OMPs after absorption with lipopolysaccharide. Sera from patients with typhoid fever contained immunoglobulin M antibodies which reacted with a protein of 28 kilodaltons and immunoglobulin G antibodies which reacted mainly with the porins, as determined by immunoblotting. These results indicate that the porins are the major immunogenic OMPs from S. typhi and that the immune response induced in the infection could be related to the protective status.

Adult↗

[Cellular and humoral immunity and nonspecific resistance factors in chronic opisthorchiasis patients during dispensary observation].

In 116 patients with opisthorchiasis running a cholecystocholangitic variant of the disease course, the characteristics of nonspecific resistance (complement, lysozyme, properdin), cell-mediated and humoral immunity (T- and B-lymphocytes, T gamma-, T mu-, O-, D-, A-cells and auto-rosette-forming cells, IgG, IgA and IgM) have been studied. Essential changes in these characteristics before and after treatment, as well as at the remote periods of dispensary observation, have been established.

Adolescent↗

Cellular and humoral immune response to hepatitis B virus structural proteins in mice after DNA-based immunization.

BACKGROUND & AIMS: Development of a broad-based cellular immune response to hepatitis B viral structural proteins may be important for recovery from infection, and lack of such responses may lead to persistent viral infection and chronic liver disease. Strategies designed to enhance the hepatitis B virus (HBV)-specific immune response may be able to reduce persistent viral infection of the liver. The aim of this study was to induce HBV-specific cellular and humoral immune responses in mice using DNA-based immunizations with the large and middle envelope and nucleocapsid proteins. METHODS: Antibodies to HBV structural proteins, T-helper-cell proliferation, and cytokine release and generation of cytotoxic T lymphocyte (CTL) activity were measured in vaccinated mice. RESULTS: Immunized mice developed high-titer antibodies against envelope and core proteins in serum. More importantly, 93% of the immunized mice produced strong inflammatory CD4+ T-cell and CD8+ CTL responses to viral proteins. CONCLUSIONS: This study shows that DNA-based vaccination will generate broad-based CTL activity as well as strong T-helper cell responses with the production of TH1-type cytokines to HBV structural proteins. Such constructs are promising candidates as antiviral agents, and these studies have defined some of the most immunogenic antigens for an immunotherapeutic approach of chronic HBV infection.

Animals↗

Induction of feline immunodeficiency virus-specific cell-mediated and humoral immune responses following immunization with a multiple antigenic peptide from the envelope V3 domain.

Cytotoxic T-cell determinants should be an important component of a vaccine against feline immunodeficiency virus (FIV). Epitope mapping studies have revealed an immunodominant neutralization epitope within the third variable (V3) domain of the viral envelope glycoprotein comprizing 17 amino acids (residues 390-406: RAISSWKQRNRWEWRPD). We have investigated the induction of FIV-specific cytotoxicity and anti-peptide antibody in cats immunized with a multiple antigenic peptide (MAP) containing this epitope. Virus-specific lymphocytotoxicity was determined using autologous or allogeneic skin fibroblasts as target cells labelled with chromium-51 and pulsed with overlapping 10 amino acid peptides. Cytotoxic effector cells derived from fresh peripheral blood were detected in five out of 10 immunized cats. The cell-mediated immune response appeared to be directed to envelope peptide 1 (RAISSWKQRN) and peptide 2 (SWKQRNRWEW), with recognition of peptide 3 (QRNRWEWRPD) in only one cat. An antibody response to the 17 amino acid peptide immunogen was detected in seven immunized cats, which was directed to envelope peptides 2 and 3. These results suggest that different epitopes may be recognized by the cell-mediated and humoral immune responses. None of the cats was protected from challenge with the Glasgow8 isolate of FIV (FIV/GL-8). This study has implications for vaccine strategies using synthetic peptides to induce virus-specific cell-mediated immune responses.

Amino Acid Sequence↗

Coimmunization of Agaricus blazei Murill extract with hepatitis B virus core protein through DNA vaccine enhances cellular and humoral immune responses.

DNA vaccines induce protective humoral and cell-mediated immune responses in several animal models. Agaricus blazei Murill (ABM) is particularly rich in polysaccharides, and has shown particularly strong results in treating and preventing cancers. The goal of this study was to investigate whether co-immunization of the fungus ABM with hepatitis B virus (HBV) core DNA vaccine could increase the immune responses. Compared with the control mice which received hepatitis B virus core antigen (HBcAg) alone, significant increase in not only the HBcAg-specific antibody response but also T cell proliferation was observed in mice which received HBcAg DNA vaccine plus ABM extract. These results suggest that ABM extract might represent an adjuvant to improve the efficacy of DNA vaccines in vivo.

Adjuvants, Immunologic↗

Human humoral immunity to hsp70 during Trypanosoma cruzi infection.

Immunologic screening of cDNA expression libraries has been widely used for the identification of DNA sequences encoding the immunologically relevant proteins of many pathogenic microorganisms. For reasons that are not entirely clear, sequences encoding 70-kDa heat shock and related proteins (hsp70), which are among the most highly conserved proteins known, have routinely been identified by this approach. Consequently, hsp70 proteins have been proposed to be involved in the autoimmune processes thought responsible for the pathogenesis of the diseases caused by some of these organisms, e.g., chronic Trypanosoma cruzi infection (Chagas' disease). Therefore, we investigated whether hsp70 might be a specific target of the human humoral immune response to T. cruzi infection, and, if so, whether humoral autoimmunity to hsp70 might play a role in pathogenesis. We found that hsp70 is indeed a major polypeptide Ag in Chagas' disease, but that the antibodies to T. cruzi hsp70 do not react with human hsp70--even though the proteins display 73% amino acid sequence identify. These results indicate that self-tolerance to hsp70 is maintained during chronic T. cruzi infection and strongly argue against a role for humoral autoimmunity to hsp70 in the pathogenesis of Chagas' disease.

Amino Acid Sequence↗

Novel regulators of the humoral immune response.

Activation of mature B cells to proliferation and terminal differentiation is a multistep process controlled mainly by macrophages and T cells. However, there is growing evidence that B cells and other factors can also regulate the humoral immune response. Here, Ferenc Uher, Eva Rajnavölgyi and Anna Erdei describe their work on the emerging role of regulatory interactions between subsets of B cells and their soluble products.

Animals↗

Effect of probiotics and breastfeeding on the bifidobacterium and lactobacillus/enterococcus microbiota and humoral immune responses.

OBJECTIVE: To assess impact of probiotics and breastfeeding on gut microecology. STUDY DESIGN: Mothers were randomized to receive placebo or Lactobacillus rhamnosus GG before delivery, with treatment of the infants after delivery. We assessed gut microbiota, humoral immune responses, and measured soluble cluster of differentiation 14 (sCD14) in colostrum in 96 infants. RESULTS: Fecal Bifidobacterium and Lactobacillus/Enterococcus counts were higher in breastfed than formula-fed infants at 6 months; P <.0001 and P=.01, respectively. At 3 months, total number of immunoglobulin (Ig)G-secreting cells in breastfed infants supplemented with probiotics exceeded those in breastfed infants receiving placebo; P=.05, and their number correlated with concentration of sCD14 in colostrum. Total numbers of IgM-, IgA-, and IgG-secreting cells at 12 months were higher in infants breastfed exclusively for at least for 3 months and supplemented with probiotics as compared with breastfed infants receiving placebo; P=.005, P=.03 and P=.04, respectively. Again, sCD14 in colostrum correlated with numbers of IgM and IgA cells; P=.05 in both. CONCLUSIONS: We found an interaction between probiotics and breastfeeding on number of Ig-secreting cells, suggesting that probiotics during breastfeeding may positively influence gut immunity.

Antibody Formation↗