Tumour necrosis factor and other cytokines in murine lupus.

Investigations into the structure, expression and functional status of cytokines, as well as on the possible utility of their agonists and antagonists as therapeutic agents in lupus, have received prominent attention. In fact, mouse strains predisposed to lupus (NZBxW, BXSB, MRL-lpr) have long constituted the primary resource to investigate the role of cytokines in autoimmunity. An additional impetus for such investigations in recent years has been provided by the discovery that T cells may be polarised during an ongoing immune response into the so called TH1 and TH2 subsets, which display distinct cytokine profiles and eVector functions. Thus, following antigen recognition, cytokines present at the site of priming together with other factors, such as type of antigen presenting cell, amount of antigen, co-stimulatory molecules, aYnity and duration of exposure direct the induction of either TH1 cells, which secrete IL2, IFNã and TNFâ, or TH2 cells, which secrete IL4, IL5, IL6, IL10 and IL13. Another cytokine, IL12, produced by activated macrophages and dendritic cells, is a strong inducer of TH1 cells in which the â-subunit of its receptor is retained but lost on TH2 cells. The former cells then provide protection from intracellular pathogens, activate phagocytes, induce IgG2a antibodies, and promote DTH responses, whereas the latter cells provide protection from extracellular pathogens, activate eosinophils, induce IgE mediated allergic reactions, and generally promote humoral responses in which IgG1 predominates. The molecular events associated with this polarisation have not been fully eludicated, but certain protooncogenes, kinases and transcription factors seem to play a part. Based on this T cell division, it has been hypothesised that organ specific autoimmune diseases such as IDDM should be mediated by TH1 cells, whereas humorally mediated autoimmune diseases such as lupus should be mediated by TH2 cells. As summarised in tables 1, 2 and 3 and reviewed below, such a paradigm does not seem to apply to lupus because both TH1 and TH2 cytokines have been found to exert profound eVects on spontaneous mouse models of this disease.