The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system white matter. The association of the disease with MHC genes, the inflammatory white matter infiltrates, similarities with animal models, and the observation that MS can be treated with immunomodulatory and immunosuppressive therapies support the hypothesis that autoimmunity plays a major role in the disease pathology. Evidence supports activated CD4⁺ myelin-reactive T cells as major mediators of the disease. In addition, a renewed interest in the possible contribution of B cells to MS immunopathology has been sparked by nonhuman primate and MS pathological studies. This review focuses on the immunopathology of MS, outlining the hypothetical steps of tolerance breakdown and the molecules that play a role in the migration of autoreactive cells to the CNS. Particular focus is given to autoreactive T cells and cytokines as well as B cells and autoantibodies and their role in CNS pathogenesis in MS.     

Impaired T cell proliferation, increased soluble death-inducing receptors and activation-induced T cell death in patients undergoing haemodialysis

Haemodialysis is a widespread option for end-stage renal disease (ESRD). Long-term success of dialysis is, however, limited by a high rate of serious bacterial and viral infections. We compared T cell functions in ESRD patients undergoing haemodialysis (n = 20), or were not dialysed and received conventional medical treatment (n = 20). Healthy volunteers (n = 15) served as controls. The T cell phenotype was examined by immunofluorescence using fluorochrome-labelled monoclonal antibodies and FACS analysis. The concentration of soluble CD95/Fas and of tumour necrosis factor-alpha receptor type 1 (sTNFR1) in the sera was quantified by ELISA. Activation-induced programmed T cell death was triggered by anti-CD3/CD28 antibodies and measured by 7-AAD staining. All immunological tests were performed at least 1 month after dialysis initiation. T cell proliferation in response to phytohaemagglutinin or anti-CD3 monoclonal antibodies was moderately diminished in non-dialysed patients and markedly reduced in haemodialysis patients compared to healthy controls (P < 0.01 and P < 0.001, respectively). In a mixed lymphocyte culture the proliferative response of T cells from dialysed patients was significantly diminished (P < 0.001). T cells of both non-dialysed and dialysed patients have augmented CD95/Fas and CD45RO expression, increased sCD95/Fas and sTNFR1 release and spontaneously undergo apoptosis. Culture of T cells from haemodialysis patients with anti-CD3/CD28 antibodies increased the proportion of CD4(+) T cells committing activation-induced cell death by a mean 7.5-fold compared to T-helper cells from non-dialysed patients (P < 0.001). Renal failure and initiation of haemodialysis results in a reduced proliferative T cell response, an aberrant state of T cell activation and heightened susceptibility of CD4(+) T cells to activation-induced cell death.     

Preferential activation of peripheral blood V gamma 9+ gamma/delta T cells by group A, B and C but not group D or F streptococci.

Previous studies have established that inactivated mycobacteria are potent and selective activators of V gamma 9+/V delta 2+ human gamma/delta T cells. Here we have analysed the proliferative response of human gamma/delta T cells to five serologically distinct groups of streptococci. While heat-inactivated streptococci of all five serogroups tested (A, B, C, D and F) induced a strong proliferative response in peripheral blood mononuclear cells (PBMC), only groups A, B and C elicited a selective activation of V gamma 9+ gamma/delta T cells in 10 (serogroup B) or 11 (serogroups A and C) of 11 tested healthy individuals. In striking contrast, groups D and F streptococci failed to activate gamma/delta T cells in nine of 11 donors and induced only a weak gamma/delta T cell response in two additional individuals. Depletion of V gamma 9+ T cells before culture completely eliminated all gamma/delta T cell responses to streptococci. These data indicate that groups A, B and C (but not D or F) streptococci can be included in the growing list of selective ligands for V gamma 9+/V delta 2+ human gamma/delta T cells.     

Absence of Epstein-Barr virus-specific, HLA class II-restricted CD4+ cytotoxic T lymphocytes in infectious mononucleosis.

Cytotoxic T lymphocytes (CTL) with the CD4+ phenotype that recognize major histocompatibility complex (MHC) class II antigens are detectable very frequently in cultures of human alloreactive or virus-specific T cells. The significance of these CD4+ CTL for an immune reaction in vivo is not clear. Since Epstein-Barr virus (EBV) transformed B cells express HLA-class I and class II antigens equally well both CD8+ and CD4+ CTL should be stimulated during an acute EBV infection. We analysed the MHC specificity and the phenotype of EBV-specific CTL from patients with infectious mononucleosis (IM). When tested directly without any previous culture, T cells from patients in the acute phase of IM showed specific MHC-restricted cytotoxicity against the autologous B cell line. Addition of a HLA class I specific monoclonal antibody (MoAb) but not of a HLA class II specific MoAb resulted in a complete blocking of the lytic activity. Cell sorting revealed that the entire cytotoxic activity was present in the CD8+ fraction whereas no specific CTL were detectable in the CD4+ fraction. The absence of cytotoxicity in CD4+ cells was not due to a lack of activation of these cells since both CD8+ and CD4+ cells were activated in situ, showing spontaneous growth in interleukin-2 (IL-2) and expressing the activation marker TP103. Frequency estimation revealed that 1/300-1/600 CD8+ but only 1/2000-1/4000 CD4+ T cells gave rise to a specific CTL colony after 10 days. If CD4+ colonies were tested repeatedly for cytotoxicity we found that CD4+ CTL acquired their cytotoxicity during in vitro culture. In addition, we isolated EBV-specific CD4+ T cell clones able to lyse their stimulator cells in the presence but not in the absence of lectin, even after a long period of culture. Taken together our results show that cytotoxicity mediated by CD4+ T cells does not play a role in an anti-viral immune response.     

Requirement of the T cell receptor for antigen presentation by T lymphocytes. Effect of envelope glycoproteins of HIV-1 on antigen presentation by T cells.

We have developed CD4+, tetanus antigen-specific T cell clones that proliferate in the presence of tetanus antigen and autologous irradiated peripheral blood leucocytes (PBL) as antigen-presenting cells (APC). There have been several reports that T cells can present antigen themselves. We have used tetanus antigen-specific T cell clones to examine the effects of envelope glycoproteins of HIV-1 on processing and presentation of antigen to T cells. Cloned T cells were pre-incubated with soluble crude preparation of tetanus antigen for 4 h at 37 degrees C, irradiated, and used as APC (T-APC). These cells could present antigen, as assessed by the ability of the autologous cloned T cells to proliferate. Resting T cells and phytohaemagglutinin-activated T cell blasts from autologous PBL could not present tetanus antigen to the responder cloned T cells. Antigen presentation by T-APC was abrogated by treating cells with anti-HLA-DR but not by anti-HLA-DQ monoclonal antibodies; treatment of tetanus antigen-pulsed T-APC with anti-tetanus antibody also blocked the ability of these cells to induce proliferation in responder T cells. Antigen presentation by cloned T cells was by a chloroquine-resistant pathway. Pretreatment of T-APC with envelope glycoprotein of HIV-1, gp120, did not affect the proliferative responses of the responder T cells. These data suggest that gp120 does not inhibit the antigen-presenting function while suppressing antigen-specific responses.     

Differential expression of binding sites for chemokine RANTES on human T lymphocytes

The C-C chemokine RANTES, a T lymphocyte chemoattractant, is considered an important mediator of inflammation, allergy, and host defense against HIV-1 infection. In this study, we investigated the modulation of binding of RANTES to T lymphocytes. Human peripheral blood CD3+ T cells, when freshly isolated from buffy-coat blood, expressed a considerable number of high-affinity binding sites for RANTES. These cells also showed significant chemotactic migration in response to RANTES in vitro. After 6–15 h incubation at 37°C, the binding of RANTES, but not of macrophage inflammatory protein-1α (MIP-1α) or of monocyte chemotactic protein-3 (MCP-3), consistently increased. Scatchard analyses indicated that the number of binding sites for RANTES increased about threefold by 15 h without any change in the affinity. The increase in RANTES binding was no longer detected by 24 h. This increase in the specific binding was mainly attributable to CD4⁺ T cells and was not associated with increased chemotactic activity of these cells in response to RANTES. Incubation with anti-CD3 antibody for 15 h markedly reduced the binding capability of T cells for RANTES and was associated with decreased chemotactic activity. On the other hand, when T cells were incubated with interleukin-2 (IL-2) for 1 week, the specific binding for all three C-C chemokines, RANTES, MIP-1α, and MCP-3 was markedly increased in comparison to cells cultured in the absence of IL-2. These results suggest that the expression of binding sites on T cells for RANTES is differentially modulated, indicating the existence of novel receptors for RANTES that do not bind MIP-1α.     

The thymus as primary site for antigen-specific T suppressor cells in neonatally induced tolerance to bovine serum albumin

The ontogeny of antigen-specific T suppressor cells in thymus and spleen was analyzed in CBA/Ca mice which were rendered tolerant as neonates by subimmunogenic doses of bovine serum albumin (low-zone tolerance). Activity of T suppressor cells from those mice was assessed by an assay in which spleen cells from animals primed with fluorescein-conjugated human gamma globulin can be stimulated in vitro to produce IgG anti-fluorescein antibodies when cultured in the presence of fluorescein-conjugated bovine serum albumin. Carrier-specific T suppressor cells appear first in the thymus (day 10), and much later (day 30) in the spleen. The data are discussed in connection with the possible role of T suppressor cells during induction of tolerance in newborn mice.