Autosomal dominant chronic mucocutaneous candidiasis and primary hypothyroidism complicated by oesophageal carcinoma.

We describe three generations of a white family with autosomal dominant chronic mucocutaneous candidiasis (CMCC) and primary hypothyroidism, which was complicated by squamous cell carcinoma (SCC) of the oesophagus in the index case. We report this family to increase awareness of this rare autosomal dominant variant of CMCC endocrinopathy syndrome associated with primary hypothyroidism without evidence of autoimmune endocrinopathy, and to highlight the risk of developing oesophageal SCC at a young age as a fatal complication of CMCC.

Impaired dendritic cell maturation and cytokine production in patients with chronic mucocutanous candidiasis with or without APECED.

Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.

Disseminated Bacillus Calmette-Guérin infection in a girl with hyperimmunoglobulin E syndrome.

Disseminated Bacillus Calmette-Guérin infection occurs in few well-defined immunodeficiencies, such as severe combined immunodeficiency, chronic granulomatous disease and paediatric acquired immunodeficiency syndrome. This severe complication of immunization against tuberculosis has been lethal in the majority of children who had primary immunodeficiency. Our patient, a 9-y-old girl with hyperimmunoglobulin E syndrome developed disseminated Bacillus Calmette-Guérin infection in infancy. Patients with hyperimmunoglobulin E syndrome (HIES) are susceptible to serious staphylococcal and fungal infections. Disseminated Bacillus Calmette-Guérin infection has not previously been reported in this rare immunodeficiency.

Cytokine production differs in children and adults.

The susceptibility of normal, healthy children to infection has long been recognized, but the underlying mechanisms are poorly understood. As adequate cytokine production is crucial for optimal immune responses, we assessed antigen and mitogen-induced cytokine production in healthy children. Our results demonstrate that healthy children differ markedly compared with adults in their ability to produce cytokines (IL-2, interferon-gamma, IL-4, and IL-6). Maximal stimulation with mitogen demonstrated impaired cytokine production with markedly lower levels of all four cytokines produced compared with adult levels. When stimulated with antigens, median levels of IL-2 and IL-4 remained lower than adult values, IL-6 production was increased as was interferon-gamma, albeit not significantly. Although the study was carried out on peripheral blood mononuclear cells that represent a restricted compartment of the immune system, these data suggest that, in healthy children, cytokine production is decreased and/or altered and could result in a suboptimal immune response, which could be one of the factors underlying increased susceptibility to infection in children.

Chronic mucocutaneous candidiasis. I. Altered antigen-stimulated IL-2, IL-4, IL-6 and interferon-gamma (IFN-gamma) production.

Patients with chronic mucocutaneous candidiasis (CMC) present with persistent infections with the opportunistic yeast Candida. Impaired cell-mediated responses to Candida have been documented in CMC patients, but the defect remains poorly understood. The importance of Th1 cytokines in resistance and Th2 in susceptibility to Candida infections has recently been demonstrated in murine models. In our studies we evaluated production of IL-2 and IFN-gamma (markers of Th1 type responses) as well as IL-4 and IL-6 (Th2 type markers) following stimulation with two kinds of Candida antigens (CAgs), polysaccharide antigens, tetanus toxoid and pokeweed mitogen. Our results demonstrate that CMC patients have impaired cytokine production upon in vitro stimulation with CAgs resulting in low or absent IL-2, increased IL-6 and either absent or increased IFN-gamma production. Cytokine production following stimulation by other antigens was unaltered. The overall cytokine-producing capacity assessed through mitogen stimulation was also intact. Addition of IFN-alpha or IFN-gamma to culture in an attempt to modify cytokine production did not have significant effects. Levels of soluble IL-6 receptors were not increased and could not account for increased IL-6 production. Our studies support the hypothesis that Candida antigens trigger a predominantly Th2 instead of a Th1 cytokine response in patients with CMC.

[Serum and urinary interleukin-6 levels in patients with primary glomerulonephritis]. / Nivo interleukina sest u serumu i urinu bolesnika s primarnim glomerulonefritisom.

Several studies have suggested that the measurement of urinary interleukin-6 (IL-6) is a helpful tool for diagnosis and monitoring the progression of glomerulonephritis. The aim of this study was to determine if IL-6 level might reflect the histological type of glomerular lesions. We performed a prospective study of 43 patients who underwent renal biopsy in our hospital. There were 35 male and 8 female patients with median age of 30.5 years (range 19-50). Included among these were 13 cases of IgA nephropathy, 11 cases of membranoproliferative glomerulonephritis, 6 cases of poststreptococcal glomerulonephritis, 6 cases of mesangial proliferative glomerulonephritis, 5 cases of membranous nephropathy and 2 cases of C3 nephritis. IL-6 was measured by ELISA (Lucernachem, Switzerland). IL-6 was not detected in the serum and rine of 15 healthy controls. IL-6 was elevated in the urine of 30 patients with different histological types of glomerular lesions (range 3.7 to 433.3 pg/ml) but was not detected in the urine of remaining 13 patients. The presence of IL-6 in the urine in absence of raised serum IL-6 suggests that urinary IL-6 was produced by the kidney. We have concluded that urinary IL-6 level can be considered as a marker of glomerulonephritis but not one that is very specific for any particular histological type of primary glomerulonephritis. Thus, the urinary IL-6 level is not a useful tool in the differential diagnosis of primary glomerulonephritis. We need further studies to determine whether urinary IL-6 level could by considered for monitoring of disease activity and therapy.

Aberrant levels of cytokines within the healing wound after burn injury.

OBJECTIVE: To study the effect of a burn injury on the course of cellular and cytokine changes in a wound and the relationship of these cytokines to the amounts of protein and collagen deposited at the site of the wound. DESIGN: A randomized control trial was done in which one group of rats were subjected to a severe burn injury. With the use of a sponge matrix model, the wound-healing parameters were evaluated. MATERIALS: A random sample of eight inbred albino Oxford rats per group were used in all experiments. INTERVENTIONS: Rats were subjected to a severe scald injury. Polyvinyl sponges were used as the wound-healing model. MAIN OUTCOME MEASURE: The obtained results implied that the wound-healing process is impaired after a severe burn injury. RESULTS: The wounds in these animals with burn injuries contained a lower number and an altered type of infiltrating cells with aberrant levels of cytokines, higher levels of interleukin-6, and lower levels of tumor necrosis factor and interleukin-1 in the fluids of the wounds. The parameters of healing (amounts of protein and collagen deposited at the site of the wound) were significantly lower in animals with burn injuries on days 7 and 14. CONCLUSION: The underlying mechanism of the impaired healing of a wound after burn injury could lie in the altered migration of inflammatory cells to the site of the wound and in the aberrant cytokine levels within the wound.

Increased activity of lymph node cells in thermal injury.

While trauma-induced suppression of T-cell responses is well documented, only few studies address lymphocyte activation. The aim of this study was to investigate the functional activity of lymph node cells in rats subjected to scald injury, proliferative activity, cytokine production, and responsiveness to exogenously added cytokines was evaluated in cells from lymph nodes draining burned tissue and from distant, nondraining lymph node cells. Results presented clearly show that lymph node cells in scalded rats are activated in vivo although the extent of proliferation and pattern of cytokine production differ: a) proliferative activity was elevated both in draining and distant lymph nodes, but was more pronounced in cells from lymph nodes draining the injured region; b) increased production of IL-2, and particularly IL-1 and IL-6 was found and coincides well with peak of proliferative activity of draining lymph node cells; IL-2 production by distant lymph node cells remained unchanged, IL-1 and IL-6 production was significantly increased coinciding with increased proliferation; c) increased responsiveness to exogenously supplied cytokines was found in draining lymph node cells, while it remained unchanged in nondraining lymph node cells. Early activation of lymphocytes demonstrated in our experiments could be one of the previously unrecognized consequences of trauma-induced immunosuppression.

Interleukin-1 in vivo modulates trauma-induced immunosuppression.

To elucidate the mechanisms underlying trauma-induced immunosuppression and decreased IL-2 production we evaluated: 1) the effect of trauma on IL-1 production at different time intervals and 2) the effect of IL-1 in vivo administration on immune functions (IL-1 production, IL2 production, NK cell cytotoxicity) in normal and traumatized mice. Experiments were performed on CBA/H mice a) subjected to scald injury (sacrificed 3 h and 6 h later) b) treated with IL-1 in vivo (human recombinant IL-1 beta 100 ng/mouse, sacrificed 21 h and 24 h later) and c) subjected to both IL-1 in vivo treatment and scald (IL-1 was given 18 h before scald, animals were sacrificed 3 h and 6 h after scald i.e. 21 h and 24 h after IL-1 administration). Our results demonstrate that trauma alone increases IL-1 production from 1 h to 24 h after trauma infliction. Recombinant IL-1 given in vivo also induces a significant rise in IL-1 production. When mice were subjected to both trauma and IL-1 in vivo treatment, the rise in IL-1 production was not additive. Trauma induced severe depression of IL-2 production which could not be overcome by in vitro addition of IL-1 to IL-2 producing splenocytes from traumatized mice. In contrast, IL-1 administered in vivo stimulated IL-2 production in normal mice, and when given prior to trauma infliction, it completely abrogated trauma-induced suppression of IL-2 production. The same effect was seen on NK cell cytotoxicity (an IL-2 dependent function).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of autologous monocytes on the pokeweed mitogen-induced generation of immunoglobulin-secreting cells in man.

The regulatory influence of autologous blood monocytes on the PWM-induced generation of Ig-secreting cells was assessed using a reverse haemolytic plaque forming cell (PFC) assay. The PWM-induced PFC responses of monocyte-depleted cells were low or absent in most cases. Addition of 12-42% freshly isolated monocytes fully reconstituted the IgM-, IgG- and IgA-PFC responses. With more monocytes added, the PFC responses declined. Monocytes precultured for 48 h supported the PFC responses of monocyte-depleted cells less well and addition of monocytes stimulated with phorbol myristate acetate (PMA) did not increase the response. The low responses of monocyte-depleted cells co-cultured with precultured monocytes were not increased by addition of supernatant from monocyte cultures. The PFC responses of mononuclear cells induced by PWM were significantly inhibited by unstimulated precultured monocytes, and to a larger degree by PMA-treated monocytes, indicating the presence of suppressor cells among the precultured monocytes. The PWM-induced thymidine incorporation by monocyte-depleted cells with precultured monocytes added was only slightly lower than that obtained with freshly isolated monocytes added, suggesting that the suppressive role of precultured monocytes was not due to cytotoxicity.

Induction and abrogation of suppressor cell function in humans: effect on B cell activation by different polyclonal activators.

In a reverse plaque forming cell (PFC) assay, the effect of concanavalin A (Con-A)-induced suppressor cells on polyclonally activated B lymphocytes was studied. Differentiation to PFC, as induced by pokeweed mitogen (PWM), Staphylococcus aureus or Epstein-Barr virus (EBV) was in all cases suppressed by the addition of ConA-pretreated cells. The EBV-stimulated cells showed the smallest PFC response and appeared least amenable to suppression. IgA-secreting cells were less suppressible than IgM- and IgG-secreting cells regardless of the polyclonal B lymphocyte activator used. The suppressor cells were radiosensitive.