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Immune complexes (w)

Inflammation and liss m? damage

Figure 2 A summary of the major cellular defects in SLE. T cell compartment, (i) Defective thymic processing, decreased production of thymic factors, (ii) Decreased numbers and dysfunction of post-thymic precursor cells (Tp). (¬°ii) Defective suppressor T cells (Ts) fail to regulate the B lymphocyte compartment, although induction of antibody production continues owing to impaired function of helper T cells (Th). (iv) Impaired interleukin 2 (IL-2) secretion and unresponsiveness causes further imbalances in the T cell populations. B cell compartment: (v) A primary B cell defect exists, (vi) Secretion of antilymphocyte or natural thymocytotoxic antibody (NTA) amplifies regulatory disorder, (vii) Immune complexes may further impair suppressor T cell function, as well as causing tissue damage. Accessory cells: (viii) Macrophages may contribute to the autoimmune process; various unusual characteristics have been observed (ix).

immunostimulatory agent isoprinosine increased PHA-induced IL-2 production by mononuclear cells, although it failed to stimulate IL-2 responsiveness.

Elevated serum levels of interferon y (IFNy) have been noted in patients with SLE, although others have reported that the production of both IFNy and IFNa is decreased. Interestingly the IFN found in lupus is an unusual form in that it is acid-labile, a hallmark of IFNy, but is neutralized with anti-IFNa antiserum.

Amongst other cytokine abnormalities it has been reported that IL-10 is increased in lupus patients. IL-10 has been shown to have a particular propensity for stimulating B cells to produce autoantibodies.

B cells Although B cell hyperresponsiveness has largely been attributed to lack of T cell regulation, there is now evidence to suggest that there is a B cell defect per se in lupus. Thus B cells from SLE patients have an intrinsic fault manifested by their inability to produce anti-influenza antibodies when sensitized in vitro. The antibodies produced by the B lymphocytes in lupus patients frequently carry common idiotypes. It is evident that switching of both antibody isotype and idiotypes may be involved in the immunopathology of lupus. Thus IgG autoantibodies are evidently more pathogenic than IgM and certain idiotypes (e.g. Id 16/6) have been found in the serum of the majority of lupus patients and in many renal biopsies.

Accessory cells Dysregulated function of accessory cells may not be the most crucial immunological lesion in the SLE disease process, but nevertheless can amplify the inflammation in several ways.

Deficiencies in the reticuloendothelial system may influence the deposition of immune complexes. An in vitro test showing a neutrophil defect has been described in SLE.

Natural killer (NK) cells are normally associated with the killing of virus-infected or tumor cells and function in combination with interferon. Although the role of the NK population in SLE has yet to be fully determined, various abnormalities have been reported including reduced numbers and functional immaturity and reduced killing capacity and insensi-tivity to interferon.

Apoptosis With the description of a transgenic mouse overproducing the proto-oncogene bcl-2 developing a lupus-like disease, anti-DNA and anti-Sm antibodies and an immune complex glomerulonephritis, much interest has focused on apoptosis in relation to SLE. Amongst a variety of hypotheses it has been suggested that some cells in lupus patients may undergo increased apoptosis, thus yielding a surfeit of nucleosomal material, but that other cells, notably the B cells, have a lower rate of apoptosis, the consequence of which is that they live longer and produce more autoantibodies. There has been considerable interest in the Fas molecule, a 43 kDa glycoprotein which is involved in inducing apoptosis in both B and T cells. In the MRL/lpr model, the lymphoproliferation mutation results in defective transcription of the gene that codes for Fas protein. However, an initial claim that 60% of lupus patients have elevated levels of the soluble Fas protein in their serum has not been confirmed by other studies and the role of this molecule in human lupus remains uncertain.

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