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BACKGROUND: It is expected that in patients with coeliac disease the small-bowel mucosal mucosa will return to normal if they adhere to a gluten-free diet (GFD). However, in many this is not the case. This study aims to determine whether this persistent villous atrophy (VA) could be due to continued ingestion of the trace amounts of gluten in 'gluten-free' foods, as defined by the WHO/FAO Codex Alimentarius. METHODS: Duodenal biopsy specimens from 89 adults with long-standing coeliac disease were examined, and the findings correlated with their form of gluten-free diet. RESULTS: In 51 subjects the duodenal specimen was normal, whereas in 38 there was villous atrophy (partial, 28; subtotal, 8; total, 2). There was no relationship between the presence or absence of VA and ingestion of either a GFD as defined by the Codex Alimentarius (Codex-GFD; 39 patients) or a GFD that contained no detectable gluten (NDG diet: 50 patients). Intraepithelial lymphocyte counts were higher, and lactase levels lower, in subjects with an abnormal biopsy specimen than in those in whom it was normal. However, within each of these biopsy groups there was no difference in these variables between patients on a Codex-GFD and those on an NDG-GFD. IgA antigliadin antibody was detected in 4 of 29 patients on a Codex-GFD and in 3 of 13 on a NDG-GFD (NS). CONCLUSION: The persistent mucosal abnormalities seen in patients with coeliac disease on a GFD are not due to the ingestion of trace amounts of gluten. The consequences of these abnormalities have yet to be determined.

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BACKGROUND: Whereas many people with coeliac disease (CD) are asymptomatic when consuming a gluten-free diet (GFD), a proportion continues to experience symptoms. The reasons for this are unclear. METHODS: Thirty-nine adult members of The Coeliac Society of New South Wales, all of whom had persistent gastrointestinal symptoms despite adhering to a GFD, were evaluated. Dietary analysis indicated that 22 (56%) were consuming a GFD as defined by the WHO/FAO Codex Alimentarius (Codex-GFD), in which foods containing up to 0.3% of protein from gluten-containing grains can be labelled as 'gluten free'. The remaining 17 were following a no detectable gluten diet (NDG)-GFD, as defined by Food Standards Australia. All subjects were required to follow a NDG-GFD during the study. Those in whom symptoms persisted after changing from a Codex-GFD and those who entered the study already on a NDG-GFD began an elimination diet followed by open and double-blind challenges to identify specific non-gluten food or food chemical intolerances. RESULTS: Of 22 patients who switched to a NDG-GFD symptoms resolved in 5 (23%) and were reduced in 10 others (45%). Thirty-one subjects commenced the elimination diet. Symptomatic improvement was experienced in 24 (77%). Subsequent food or food chemical challenges resulted in a mean of five positive challenges per individual. Diarrhoea was the most commonly provoked symptom, followed by headache, nausea, and flatulence. Symptoms were especially provoked by amine, salicylate and soy. CONCLUSION: The consumption of trace amounts of gluten, traditionally allowed in a Codex-GFD, may be responsible for the continuing symptoms seen in some patients with CD. Further investigation for non-gluten food intolerances should follow if symptoms persist after adherence to a NDG-GFD.

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Twentieth century allergy has caught the popular imagination. This article looks at the nature of the problem and whether it is in fact a true allergy. A practical approach to clinical assessment is made and advice as to management is offered.

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Self-tolerance to a transgene-encoded protein, hen egg lysozyme, was examined in the T and B cell repertoires of a series of lines of transgenic mice that expressed different serum concentrations of soluble lysozyme. T cells were tolerant in all lines in which lysozyme was expressed irrespective of the antigen concentration, whereas B cell tolerance did not occur when the serum lysozyme concentration was less than 1.5 nanograms per milliliter (0.1 nM). Induction of elevated transgene expression could restore B cell tolerance. These findings support the hypothesis that autoimmune disease may in some instances arise through a bypass of T cell tolerance.

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Immunological tolerance has been demonstrated in double-transgenic mice expressing the genes for a neo-self antigen, hen egg lysozyme, and a high affinity anti-lysozyme antibody. The majority of anti-lysozyme B-cells did not undergo clonal deletion, but were no longer able to secrete anti-lysozyme antibody and displayed markedly reduced levels of surface IgM while continuing to express high levels of surface IgD. These findings indicate that self tolerance may result from mechanisms other than clonal deletion, and are consistent with the hypothesis that IgD may have a unique role in B-cell tolerance.

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The potential role of suppressor T cells (Ts) in the induction of self-tolerance was investigated by eliminating I-J+ cells during ontogeny (I-J antigens are encoded by the I-J subregion of the murine major histocompatibility complex). To achieve this, F1 mice were exposed to anti-I-J antibodies via the transplacental route by mating B10.A(3R) females, preimmunized with B10.A(5R) cells, with CBA males. At 6 weeks of age, the offspring were injected with rat erythrocytes (RRBC) to induce erythrocyte autoantibodies. By comparison with age-matched controls, Ts-depleted mice produced significantly higher titers of autoantibody, whereas there was no difference in the antibody response of the two groups to the foreign determinants on the RRBC. The selective increase in autoantibody production was mirrored at the clonal level by the appearance of self-reactive B-cell hybridomas after fusion of RRBC-immune spleen cells with the NS-1 cell line. On the other hand, when helper cell function of RRBC-primed cells was measured in a T-cell proliferative assay, Ts depletion in utero resulted in enhanced T-cell activity to nonself (RRBC) but not to self (mouse erythrocyte) determinants. Thus, helper T cells recognizing nonself determinants on RRBC appeared to be responsible for activating self-specific B cells, presumably through linked recognition of different epitopes on mouse erythrocytes. Taken together, these findings indicate that elimination of I-J+ cells during ontogeny can lead to the appearance and activation of "forbidden" B-cell clones and points to a central role for Ts in induction as well as maintenance of self-tolerance.

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A patient with Bruton's X-linked hypogammaglobulinemia, who developed the typical syndrome associated with systemic echovirus 3 infection whilst on routine intramuscular gammaglobulin replacement therapy, is described. Following regular infusions of specific antibody-containing plasma from his spouse, he has shown sustained clinical improvement over a period of two years, and is, therefore, one of the very rare cases with this syndrome to survive for more than a few months.

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Regulation of the antibody response to the hapten, dinitrophenyl (DNP), was studied using human gammaglobulin (HGG) as the carrier in an adoptive transfer system. CBA mice immunized at least 4 weeks previously to HGG or DNP served as the source of T helper cells and hapten-primed B cells, respectively. The addition of spleen cells from donors recently primed to HGG in immunogenic form (aHGG) suppressed the collaborative anti-DNP PFC response as effectively as cells from tolerant donors. The suppressive effect was antigen-specific and was mediated by a T cell with the same phenotype (Ly-1-, Ly-23+, Ia+) and induction kinetics as those previously identified in HGG-tolerant animals. During the primary response to HGG an early burst of helper activity was detected initially, followed by a wave of suppression which peaked at day 7 and subsequently waned, allowing adoptive helper function to reappear during the third week. When previously immunized animals were boosted with soluble HGG after primary suppression had waned, the sequential appearance of helper and suppressor activity was accelerated, and the secondary suppressive effect was more profound and of longer duration than that observed during a primary response. Although helper activity was not apparent during the peak of secondary suppression, helper T cells (Th) had not been functionally deleted since treatment of the donor spleen cells with anti-Ia and complement to deplete suppressor T cells (Ts) before adoptive transfer resulted in significant augmentation of the anti-DNP response. The secondary suppressive effect was formally shown to be mediated by activated Ts effector cells bearing the same surface markers as the cells responsible for primary suppression. The results suggest that the Ts population, like other lymphocyte subsets, contain memory cells capable of rapid reexpression of effector function upon secondary exposure to antigen. These cells are considered to be of a major importance in maintenance of immune homeostasis.

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Only one case of the acquired immune deficiency syndrome (AIDS) has been conclusively documented in Australia despite a large at-risk population and the endemic nature of the syndrome in the United States. In this article, the cases of two homosexual men who had the clinical and laboratory features of a prodromal form of AIDS are presented. Such cases should serve to alert the medical profession and public health authorities to the possible existence of the syndrome in Australia.

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The transient presence of suppressor T cell (Ts) activity in high-dose tolerance to human gamma globulin (HGG), and its (apparent) absence in low-dose tolerance, have been advanced as strong evidence against the concept that Ts play an important role in maintenance of immunological unresponsiveness. To analyze this question, CBA mice were exposed to high or low doses of deaggregated HGG (dHGG) and later challenged with HGG in immunogenic form (aHGG); their capacity to mount a primary or secondary suppressive response was assessed in an adoptive hapten-carrier system. Primary suppression reached a maximum 7 d after high-dose tolerance induction and gradually waned thereafter, being no longer detectable by day 30-35. Subsequent challenge of tolerant mice with aHGG, however, led to a rapid reactivation of suppression that bore the hallmarks of an anamnestic secondary response, and this effect was still demonstrable 135 d after tolerance induction. It was also shown that a single low dose of dHGG was capable of generating memory for suppression despite the absence of detectable primary suppression, indicating that the latter is not a prerequisite for induction of memory cells. The results were interpreted as indicating that tolerance, like immunity, is a manifestation of specific immunological memory. If tolerance to self-antigens is maintained by a similar mechanism, it would be expected that memory Ts could be induced during the early stages of fetal development. Mice were therefore exposed to tolerogen in utero by injection of their mothers with dHGG at day 7 of gestation, and were assessed at various times after birth for the capacity to exhibit primary or secondary suppression in adoptive transfer. Nonspecific suppression masked any specific effects during the first 5 wk of life. Antigen-specific, primary suppression was demonstrable subsequently until 10-12 wk of age, and if the animals were challenged with aHGG before transfer an anamnestic secondary suppressive response could be elicited up to 6 mo of age. These observations are consistent with the notion that memory Ts may play an important role in the maintenance of self-tolerance.

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