Dale G. Ando

Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy

Experimental allergic encephalomyelitis (EAE) is a paralytic autoimmune disease induced in susceptible animals by active immunization with myelin basic protein (MBP) or by passive transfer of MBP-specific T helper (TH) lymphocytes. We have analyzed the T cell receptor genes of 33 clonally distinct TH cells specific for a nonapeptide of MBP inducing EAE in B10.PL (H-2u) mice. All 33 TH cells used two alpha variable gene segments (V alpha 2.3, 61%; V alpha 4.2, 39%), the same alpha joining gene segment (J alpha 39), and two V beta and J beta gene segments (V beta 8.2-J beta 2.6, 79%; V beta 13-J beta 2.2, 21%). The anti-V beta 8 monoclonal antibody F23.1 was found to block completely recognition of the nonapeptide by V beta 8 TH cells in vitro and to reduce significantly the susceptibility of B10.PL mice to peptide-induced EAE.

Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype

T helper cells reactive to myelin basic protein are clearly implicated in the pathogenesis of murine EAE. We have developed a T cell line, BML-1 that (1) is reactive to the encephalitogenic amino terminal nonapeptide (1-9NAC) of MBP, (2) is I-Au restricted, and (3) induces relapsing EAE in B10.PL (H-2u) mice. Measurement of the lymphokine profile of BML-1 revealed secretion of IL-2, interferon-gamma and lymphotoxin but not IL-4. This profile is consistent with the Th1/DTH subtype. Coculture of BML-1 with MBP-primed B cells shows that BML-1 does not provide significant helper function in vitro. In addition, BML-1 secretion of interferon-gamma was found to inhibit LPS-induced anti-MBP antibody responses. This suggested that anti-MBP antibodies may not be necessary for induction of EAE. Sera from mice, in which severe disease was induced with the 1-9NAC peptide and Bordetella pertussis, showed no development of serum antibodies to MBP. These data show that MBP-reactive Th cells of the Th-1/DTH subtype can induce EAE and do not provide Th function for anti-MBP responses and that serum anti-MBP antibodies are not found in peptide 1-9NAC-induced disease. T cell lines specific for encephalitogenic epitopes and characterized for lymphokine secretion will provide a useful tool for understanding the role of T cells in the induction of EAE.

Clinical significance of a single test for anti-cardiolipin antibodies in patients with systemic lupus erythematosus

PURPOSE Clinicians have difficulty interpreting results of tests for anti-cardiolipin antibodies (aCL) because of conflicting reports of the clinical associations of these antibodies in patients with systemic lupus erythematosus (SLE). We therefore decided to evaluate the clinical associations of aCL in an effort to facilitate interpretation of single reports of either positive or negative test results. We also assessed the role of estrogen on the development of aCL. PATIENTS AND METHODS The study population consisted of 85 consecutive outpatients with SLE and 40 control subjects. Serum samples and clinical and laboratory data were obtained from each patient and control. Testing for aCL was performed using a standardized enzyme-linked immunoabsorbent assay developed at an international workshop. RESULTS The presence of aCL was documented in 42.4 percent of patients with SLE and 7.5 percent of control subjects. In patients with SLE, these antibodies were significantly associated with thrombosis, fetal loss, and thrombocytopenia, but not with other manifestations. Measurement of all isotypes optimized clinical correlations. Titers did not add clinical utility. Fluctuations of levels of aCL occurred, making it difficult to interpret a single negative result. Among control subjects, the presence of aCL was not significantly more common in women who used oral contraceptives. CONCLUSION Our findings suggest that positive results of testing for aCL correlate with a predisposition for thrombosis, fetal loss, and thrombocytopenia in patients with SLE; however, the test is not predictive for other clinical manifestations of SLE, including activity and severity of disease. We believe that measurement of all isotypes of aCL should be performed in patients with SLE considering pregnancy, to identify those with a high risk of fetal loss, and in SLE patients with a thrombotic episode.

Idiotypic spreading promotes the production of pathogenic autoantibodies

We propose that a major immunoregulatory abnormality in murine and human autoantibody-mediated disease is idiotypic spreading. By this mechanism, B cells with the genetic information to produce immunoglobulin (Ig) bearing certain public idiotypes (Ids) are selectively upregulated, probably by Id-recognizing helper T cells. The model in which we are testing the hypothesis is systemic lupus erythematosus (SLE) in humans and NZB/NZW F1 (BW) female mice. Recent experiments have shown that the number of public Ids expressed on the Ig of nephritic BW mice is quite restricted. IdX is the dominant Id on serum Ig; IdGN1 and IdGN2 are also common. All three Ids were initially derived from spontaneous antibodies to DNA. Together the three are present on 85% of the total Ig repertoire. Such restriction suggests idiotypic spreading. In glomerular Ig deposits from nephritic BW mice, IdGN1 and IdGN2 are found on 45% of the total Ig: IdX is present in minute amounts. Furthermore, suppression of IdGNs by administration of anti-IdGN1 to BW mice resulted in significant delay in the onset of nephritis, but the IdGNs escaped from control and eventually caused a fatal nephritis. Finally, studies of glomerular Ig deposits in renal biopsies of patients with SLE have shown that IdGN2 dominates such Ig, being present in 76% of renal biopsies from SLE patients and in 6% from patients with non-lupus immune nephritis. Therefore, we have concluded that IdGN1 and IdGN2 are markers of nephritogenic subsets of autoantibodies and are probably the products of idiotypic spreading most likely to cause disease. Finally, after a review of recent experiments suggesting the dominance of autoreactive, Mossman Type 2 T helper cells in nephritic BW mice, it is hypothesized that autoreactive, IdGN-recognizing helper T cells may be central to the sustained upregulation of pathogenic autoantibodies in murine and human SLE.

T cell up-regulation of B cells via their idiotypes contributing to the development of systemic lupus erythematosus: A hypothesis

A mechanism for sustained production of pathogenic autoantibody subsets in patients and mice with systemic lupus erythematosus may be centered on selective up-regulation of B cells bearing certain idiotypes. Public idiotypes are characteristic of some autoantibodies, including anti-DNA. Evidence is reviewed that suggests that immunoglobulins bearing certain public idiotypes, such as IdGN2, contain autoantibody subsets that are nephritogenic in human systemic lupus erythematosus and in New Zealand black/New Zealand white F1 mice. Up-regulation of such cells could promote development of nephritis. Work from several laboratories has shown that production of immunoglobulin G antibodies to DNA depends upon T cell help. In New Zealand black/New Zealand white F1 mice, cloned T cells are dominated by autoreactive cells that produce B cell growth factors. We suggest that this sustained release of B cell growth factors combined with selection by T helper cells for B cells bearing IdGN2 are a major mechanism for sustained up-regulation of nephritogenic subsets of autoantibodies.

Idiotype selection is an immunoregulatory mechanism which contributes to the pathogenesis of systemic lupus erythematosus

Abstract Several experiments are reviewed to support the following suggestions: (1) Idiotypes can be used to identify pathogenic autoantibodies in murine and human systemic lupus erythematosus; (2) Those idiotypes are targets for immune upregulation which causes them to expand and dominate immunoglobulin responses; (3) Those idiotypes require autoreactive T-cell help; and (4) Both T cells and B cells participating in this response are polyclonal. These observations are used to construct an hypothesis to explain the sustained production of pathogenic autoantibody subsets.

Idiotype Selection is an Immunoregulatory Mechanism which Contributes to the Pathogenesis of Systemic Lupus Erythematosus

Several experiments are reviewed to support the following suggestions: (1) Idiotypes can be used to identify pathogenic autoantibodies in murine and human systemic lupus erythematosus; (2) Those idiotypes are targets for immune upregulation which causes them to expand and dominate immunoglobulin responses; (3) Those idiotypes require autoreactive T-cell help; and (4) Both T cells and B cells participating in this response are polyclonal. These observations are used to construct an hypothesis to explain the sustained production of pathogenic autoantibody subsets.