Breakdown of T-cell ignorance: The tolerance failure responsible for mainstream autoimmune diseases?

This article explores the possibility that the major autoimmune diseases come about because of the breakdown of T lymphocyte ignorance - that state in which antigen and lymphocyte have never come together in such a way as to induce tolerance or an immune response. By use of transgenic technique to place a foreign antigen/peptide in various mouse tissues the widespread occurrence of ignorance has been observed and information obtained on when it is likely to occur. Now, with the advent of tetramer technique to enrich specific T cells and the recognition of lymphocyte markers indicating whether or not antigen interaction has taken place, ignorance of genuine self-antigens is being examined in mouse and man. In the absence of thymic deletion it seems that tolerance to self-antigens is brought about either by T cell ignorance or T cell regulatory control. The initiating factor in these major diseases is likely to be a change in the condition of the antigen leading to tolerance failure. There is evidence that it is ignorance that breaks down in Type 1 diabetes and systemic lupus erythematosus. If this proves a general rule, it may be because ignorance is the tolerance mechanism most vulnerable to subversion.

Anomalies in the ionic properties of serum albumin.

The documented difference in the isoionic points of native and unfolded serum albumins is revisited with computational methods. Good agreement between calculated and measured DeltapIs is found, with the molecular origin appearing to reside in a diverse set of carboxyl group titrations. Although histidine ionization plays only a minor role in bringing about the DeltapI, the identification of three histidine residues with low computed pK(a)s (around pH 5) suggests an explanation for the mismatch between experimentally derived group pK(a)s and the pI of the native protein. Computed electrostatic properties (including pI) of native serum albumins are compared with a set of 178 nonenzyme proteins. We find that the degree of interdigitation of positive and negative charges is extreme for serum albumin, and discuss the relationship to protein solubility and pH-dependent structural transitions.

A two-step hypothesis for the appearance of autoimmune disease.

Two phenomena are likely to be central to an understanding of how autoimmune disease comes about--immunological tolerance and ignorance. Yet ignorance, the state where antigen and lymphocyte have never come together in such a way as to induce either tolerance or an immune response, is often ignored in recent discussion. This article reviews evidence that has led to the suggestion that most autoimmune disease arises from termination of ignorance. Termination could come about in a number of ways. Self-antigens may be made available to the immune system by infective or physical tissue damage or by a defect in the phagocytic removal of apoptotic cells. Moreover, infectious agents may bring an end to ignorance by mimicry or by their ability to induce co-stimulatory activity as a consequence of inflammation. Since loss of ignorance could be a relatively common occurrence it is suggested that a back-up would be essential. This could be a role for regulatory T cells, possibly those expressing both CD4 and CD25. Two steps may thus be necessary for the appearance of autoimmune disease--loss of ignorance followed by failure of regulatory T cells to control anti-self effector T cells.

Proliferation assay amplification by IL-2 in model primary and recall antigen systems.

BACKGROUND: It can be difficult to register a weak proliferative response of T lymphocytes to an antigen, particularly in a simple culture system of peripheral blood mononuclear cells (PBMC). Here we assess the usefulness of the cytokine IL-2 in amplifying such a response. METHODS: PBMC from healthy donors were cultured in the presence or absence of keyhole limpet haemocyanin (KLH), an antigen to which people have not been previously exposed. IL-2 was added from the beginning or on the fifth day of culture. Proliferation was determined by incorporation of tritiated thymidine at eight days. The recall antigen, tuberculin PPD, provided a positive control. RESULTS: IL-2 added at the beginning of culture can induce extremely high levels of proliferation even in the absence of antigen. However, when added on the fifth day it allowed the clear observation of a proliferative response to KLH that was barely detectable in its absence. Added late it was similarly able to boost low responses to PPD and to the mitogens lipopolysaccharide and poly(I:C), but it had no such effect with pokeweed mitogen. CONCLUSIONS: IL-2 added late in culture is highly effective in increasing the sensitivity of T lymphocyte proliferative assays.

Two paradoxes and a surprise on the road to an understanding of systemic lupus erythematosus.

Whereas systemic lupus erythematosus (SLE) as normally encountered results from the coming together of a complex mix of genetic and environmental factors, SLE also develops in virtually all those rare people who lack a functional gene for the first component of complement (C1q). The pathogenic IgG antibodies against double-stranded DNA characteristic of the disease are made in response to nucleosomes - the package of DNA and histone molecules forming the unit structure of chromatin - which are present in apoptotic cells. Analysis of the C1q phenomenon illuminates the arrangements that are normally in place to ensure tolerance is maintained to nucleosomal antigens. Surprisingly in view of the high level of apoptosis occurring in the thymus, it appears that anti-histone helper T cells, which are likely to be required for IgG anti-DNA production, are not deleted in the thymus. It seems rather that tolerance is maintained by non-availability of antigen brought about by the highly efficient C1q-dependent phagocytosis of apoptotic cells. This 'immunological ignorance' may be backed up by mechanisms of peripheral tolerance if antigen does become available. Idiopathic SLE may arise when apoptotic cell clearance is sub-optimal, making clearance a promising target for therapy.

Natural killer T cells in families of patients with systemic lupus erythematosus: their possible role in regulation of IGG production.

OBJECTIVE: To determine whether there is a link between the frequency of natural killer T (NKT) cells and high levels of IgG in patients with systemic lupus erythematosus (SLE) and their relatives. METHODS: Blood samples were obtained from patients with SLE, their first-degree relatives, patients with rheumatoid arthritis (RA), and healthy control subjects. The frequency of NKT cells (defined as CD56+ T cells) was expressed as a percentage of total blood lymphocytes. Plasma levels of total IgG and IgM, and IgG antibodies to double-stranded DNA (dsDNA) were determined. RESULTS: The frequency of NKT cells was lower in patients with SLE than in control subjects. No such decrease was observed in the relatives of patients with SLE or in patients with RA. High levels of IgG were observed in both patients with SLE and their relatives, while low levels of IgM were observed in these same groups. In relatives of patients with SLE, an inverse correlation between the frequency of NKT cells and IgG levels was observed. Moreover, raised levels of IgG in patients with SLE and their relatives and high levels of IgG anti-dsDNA in patients were associated with low frequencies of NKT cells. CONCLUSION: These results suggest that NKT cells have an important role in the regulation of IgG production, although NKT cells with invariant T cell receptors may not necessarily be involved. NKT cells in the setting of SLE could lack the cytokine stimulus from NK or other cells that is needed to exert control on IgG production. Enhancement of NKT cell activity may provide a novel basis for therapy in SLE.