A great deal of literature is devoted to the description of the multiple and frequently contradictory immune cell abnormalities encountered in SLE, since aberrations of the immune cells are believed to play a major role in the pathogenesis of lupus. These studies have improved our understanding of the disease, helped us design novel treatments, and guided the search for the involved genes. Although the cellular aberrations in LE may reflect secondary effects, therapeutic modulation of the cellular abnormal ities represents a plausible way to improve the management of patients with LE (Tsokos and Boumbas 2002).
Monocytes from patients with LE display a variety of abnormalities, including decreases in phagocytic activity, IL-1 production, expression of surface human leukocyte antigen (HLA)-DR, and accessory function for T-cell activation. In addition, LE monocytes fail to express the co-stimulatory B7 molecules after activation. These defects may partially explain the defective responses of lupus T cells to nominal antigens. In contrast, peripheral blood monocytes from patients with LE display increased rates of spontaneous apoptosis and can contribute to the increased levels of circulating autoantigens. Decreased phagocytic function may increase susceptibility of patients with LE to infections.
T-cell abnormalities are crucial in the pathogenesis of the disease because they regulate B-cell function, and the production of most of the pathogenic autoantibodies is T-cell dependent. T-lymphocyte abnormalities in patients with LE have been reviewed. Human studies of lupus lymphocyte biology are limited to peripheral blood lymphocytes and, in general, have established two apparently opposing (T-cell enigma) phenomena: the existence of activated T cells that provide excessive help to B cells to produce autoantibodies and yet the inability to respond in vitro to nominal antigens and produce IL-2.
The presence of activated T cells in the peripheral blood of patients with LE has been inferred from the presence of increased numbers of cells expressing DR+ antigens and the expression of increased levels of c-myc messenger RNA (mRNA). Studies of hprt gene-mutated T cells have provided evidence for the existence of rapidly dividing T cells in the peripheral blood of patients with LE.
The existence of T cells that provide help to B cells to produce autoantibodies has been shown clearly in studies of IL-2-expanded lines and clones. Specifically, IL-2-expanded T-cell lines established from patients with lupus nephritis helped autolo-gous B cells produce cationic anti-DNA antibodies. Most of the T-helper cell lines were CD4+, whereas a small fraction were ap TCR+ CD4- CD8- and yô TCR+. Clones reactive with the presumptive autoantigen small nuclear ribonucleoprotein (snRNP) have been established from both patients with LE and healthy individuals who carry the HLA-DR2 or HLA-DR4 genotypes after stimulation of peripheral blood MNCs with IL-2 and snRNP and they were found to frequently use the Vp6 TCR gene.
Lupus T cells have been shown to produce decreased amounts of IL-2. Both CD4+ and CD8+ cells are responsible for this deficiency. Decreased IL-2 secretion, in vitro, by lupus cells correlates with increased disease activity, lack of previous treatment, and increased numbers of spontaneously immunoglobulin-secreting B cells.
Peripheral blood MNCs from patients with LE produce less interferon (IFN)-y spontaneously and after stimulation with phytohemagglutinin or IL-2 or certain viruses. Decreased IFN-y production may contribute to a higher incidence of infections in patients with SLE. These findings contrast reports of patients with rheumatoid arthritis who developed LE after systemic administration of IFN-y, suggesting that IFN-y may promote autoimmunity. Lymphocytes from lupus-prone mice express increased levels of IFN-y mRNA, and IFN-y may promote autoimmunity by enhancing the expression of autoantigens.
The most important function of IL-6 is the promotion of immunoglobulin production by activated B cells and Epstein-Barr virus (EBV)-transformed B cells. Lupus
MNCs express high levels of mRNA for IL-6. The increased levels of IL-6 that were reported in the cerebrospinal fluid of patients with central nervous system involvement fluctuated with disease activity and may be involved in disease pathology.
Several studies have shown convincingly that IL-10 production is significantly elevated in patients with SLE and that IL-10 overproduction is implicated in the generation of anti-DNA antibodies. Up-regulated IL-10 production characterizes not only patients with LE but also healthy members of lupus multiplex families as well as affected first- and even second-degree relatives of patients with SLE. Treatment of SCID mice transplanted with human lupus MNCs with an anti-IL-10 antibody caused diminished production of anti-dsDNA antibodies.
The previously cited studies indicate that SLE is characterized by an imbalance in the ratio of type 1 (IFN-y and IL-2)-type 2 (IL-4, IL-5, IL-6, and IL-10) cytokine-secreting MNCs. However, it is simplistic at this point to state that human lupus is a Th2 disease when there is evidence that even in NZB/NZW mice both type 2 (IL-4) and type 1 (IFN-y and IL-12) lymphokines are needed for expression of the disease.
In contrast to the circulating T-cell pool, B cells from patients with LE are not numerically decreased but display increased proliferation rates and spontaneously secrete increased amounts of immunoglobulin, including autoantibodies. The amount of spontaneously released immunoglobulin from lupus B cells accurately correlates with disease activity. Polyclonal hypergammaglobulinemia is common in patients with SLE.
Although freshly isolated B cells and CD4+ and CD8+ T-lymphocyte subpopulations from patients with LE express higher levels of Fas antigen compared with normal cells, mitogenic stimulation of cell subsets causes normal Fas antigen up-regulation. The increased expression of Fas is accompanied by higher rates of spontaneous apoptosis. Activated T cells from patients with LE are relatively resistant to a TCR-mediated death stimulus, which may lead to prolonged survival of activated autore-active cells.
The CD40-CD40 ligand (CD40L) interaction seems to be aberrant in lupus. Although the number of circulating CD40L+ T cells in patients with LE is not increased compared with that in healthy individuals, its induction in lupus CD4+ and CD8+ T cells is both enhanced and sustained. Moreover,it was reported that lupus B cells unexpectedly express CD40L on stimulation in an equally intense manner as T cells. This abnormally regulated molecule in lupus lymphocytes is still functional because anti-CD40L monoclonal antibody inhibited the production of anti-DNA antibodies, and lupus CD40L+ cells induced the expression of CD80 (B7-1) in a B-cell line. The importance of this interaction in SLE is underscored by experiments showing that administration of a single dose of anti-CD40L monoclonal antibody in mice with lupus caused significant delay in the appearance of nephritis and substantially improved the survival of such animals without compromising the nonautoimmune response.
Abnormalities in the expression of CD80 and CD86 on the cell surface of peripheral blood B cells from patients with SLE have also been reported. Levels of CD86 expression on resting and activated lupus B cells were greater than the levels of normal B cells. CD80 was also significantly overexpressed in activated but not in resting B cells from patients with LE. Therefore, overexpression of co-stimulatory molecules on circulating B cells in patients with SLE may play a role in the continuous autore-active T-cell help to lupus B cells, leading to the production of autoantibodies.
Non-B-cell antigen-presenting cells from patients with LE fail to up-regulate in vitro surface expression of CD80 after stimulation with IFNy in a disease-specific fashion. Replenishment of functional CD80 molecules in the culture environment significantly increased the responses of SLE T cells to tetanus toxoid and to an anti-CD3 antibody. Similarly, the decreased responses of lupus T cells to anti-CD2 antibody are reversed in the presence of CD28-mediated stimulation.
T lymphocytes may express abnormally high levels of surface molecules that facilitate attachment to endothelial or other cells. Certain pairs of molecules are involved exclusively in providing the co-stimulatory signal to T cells, whereas other pairs of molecules are involved in cell co-stimulation and adhesion/homing. Distinct sets of surface molecules participate in the cell-cell and cell-matrix adhesion process. Members of the pi-integrin family of adhesion molecules are major adhesive receptors for the extracellular matrix, and members of the p2-integrin family (VLA4 and VLA3) are involved in cell-cell and cell-extracellular matrix adhesion.
Expression of adhesion molecules is up-regulated in various disease conditions, such as atherosclerosis, inflammation, and rheumatoid arthritis. VLA4 and LFA1 are overexpressed on the surface membrane of SLE lymphocytes. Interestingly, VLA4 is overexpressed only in lymphocytes from patients with vasculi-tis. Lymphocytes from these patients show increased adhesion to cord vein endo-thelial cells (see Chap. 19).
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