Biomedical subjects

A F Ochsenbein

Publications and source records attributed to A F Ochsenbein.

22 records · Page 2Linked to original sources

PubMed1999

Role of dendritic cells in the induction and maintenance of autoimmune diseases.

Autoimmune diseases are characterised by the loss of tolerance against self-determinants, activation of autoreactive lymphocytes and pathological damage to single or multiple organs. The mechanisms by which autoimmune responses are triggered and activation of autoreactive lymphocytes is initiated and maintained are not yet fully understood. Translocation of previously immunologically ignored antigens from the periphery to secondary lymphoid organs is probably a key step in the initiation of autoimmunity. Antigen transport and primary sensitisation of T lymphocytes is mainly mediated by dendritic cells which reside in peripheral non-lymphoid tissues and maintain a continuous gradient of antigens towards secondary lymphoid tissues. In the transgenic rat insulin promoter-glycoprotein model of autoimmune diabetes, dendritic cell (DC)-mediated antigen transport initiates an autoimmune response against a pancreatic neoself-antigen. Dose and timing of antigen delivery by DC and turnover of antigenic peptides presented by DC are the main parameters regulating the outcome of autoimmune diabetes in this model system. An important sequel of continued antigenic stimulation via DC is the formation of lymphoid structures in the pancreas. Thus, appropriate and repeated activation of cytotoxic T lymphocytes by DC, in concert with local inflammatory processes leading to formation of organised lymphoid tissue in the target organ, is likely to be crucial in the development of destructive autoimmunity. Therapeutic intervention to selectively manipulate antigen transport by dendritic cells or to influence antigen presentation may prove beneficial for the treatment of autoimmune diseases. Furthermore, the capacity of DC to induce potent antiself responses might have implications for the use of DC presenting self-antigens in treatment of established tumours.

Animals↗

PubMed1998

IgD can largely substitute for loss of IgM function in B cells.

The mu and delta heavy chains of IgM and IgD, the first antibody isotypes expressed during bone-marrow B-cell development, are encoded by a common transcription unit. Expression of the mu chain on the surface of late pre-B cells allows their further development to immature B cells. Coexpression of the delta chain and emigration of the immature B cells to the periphery eventually leads to the development of naive mature IgM/IgD double-positive cells. Although IgM is important in driving B-cell development, the contribution of IgD is not clear. Here we investigate the function of IgD. We generated mice deficient in IgM (IgM-/- mice) by deleting the mu region in embryonic stem cells. IgM-/- mice showed normal B-cell development and maturation, with IgD replacing membrane-bound and secretory IgM. Moreover, specific B-cell responses and isotype class switches occurred during immunization or infection. In contrast to mice deficient in B cells, IgM-/- mice survived infection with vesicular stomatitis virus by developing neutralizing immunoglobulins, but they were more susceptible than wild-type controls with delayed specific immunoglobulin responses. These data lead us to conclude that IgD is largely able to substitute for IgM functions.

Animals↗

PubMed1998

T-cell independent IgM and enduring protective IgG antibodies induced by chimeric measles viruses.

B-cell activation depends on the intensity of B-cell receptor cross-linking. Studies of haptenated antigens and vesicular stomatitis virus (VSV) have demonstrated a correlation between antigen repetitiveness and the degree to which B-cell activation is independent of T cells. Here, we compare neutralizing antibody responses to inactivated VSV with those to two inactivated human pathogenic viruses: highly cytopathic poliovirus (PV) and poorly cytopathic measles virus (MV). The rigidly structured PV efficiently induced neutralizing IgM antibodies independent of T cells. In contrast, neutralizing antibodies to the pleomorphic MV were dependent on helper T cells. To test whether this resulted from the differences in virus structure or the capacity of MV to induce cell fusion and/or immunosuppression, we analyzed antibody responses to chimeric MV expressing VSV glycoprotein instead of MV fusion protein and hemagglutinin. IgM antibodies were independent of T cells; in addition, we found IgG responses dependent on T-cell help that were enduring and protective against lethal VSV infection. Because chimeric MV viruses look like MV ultrastructurally, we conclude that not only structural differences in the envelope but also the ability of MV to induce immunosuppression may limit its capacity to directly activate B cells. These findings are relevant for our understanding of B-cell activation by two prototypic human pathogenic viruses and for the design of new recombinant vaccines.

Animals↗

PubMed1994

Transcapillary escape rate of albumin positively correlates with plasma albumin concentration in acute but not in chronic inflammatory disease.

The relationship among "negative" plasma acute-phase proteins (APP), ie, albumin, prealbumin, and transferrin, and "positive" APP, ie, C-reactive protein (CRP), fibrinogen, and orosomucoid, was investigated in patients with acute infectious disease (n = 8) and in patients with chronic malignant disease (n = 9). In addition, the transcapillary escape rate (TER) and outflux (J(alb)) of albumin were investigated using an intravenous injection of 2 microCi 125I-albumin. Interleukin-6 (IL-6) plasma concentrations were measured with an enzyme immunoassay. In the majority of patients, negative APP were decreased, whereas positive APP were increased. However, in patients with infectious disease, there were no significant correlations between any of the negative and positive APP. Also, in patients with infectious disease, TER was increased to 8.6 +/- 3.4%/h (mean +/- SD), and J(alb) to 114 +/- 60 mg/kg/h, compared with normal values of 4.3 +/- 2.6%/h and 108 +/- 7 mg/kg/h, respectively. Unexpectedly, there was a significant positive correlation between plasma albumin and both TER (r = .8279, P = .011) and J(alb) (r = .8683, P = .005). In patients with malignomas, significant correlations within negative and positive APP and inverse correlations between negative and positive APP resulted. Malignant disease induced only a slight elevation in TER (6.6 +/- 2.4%/h), J(alb) was within normal limits (92 +/- 35 mg/kg/h), and no correlations between plasma albumin concentrations and TER (r = -.0174, P = .97) or J(alb) (r = .4090, P = .27) were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗