Context:Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse.Objective:To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996–2016).Patients:All known Norwegian patients with APS1.Results:Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes.Conclusions:Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

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BackgroundMagnesium (Mg) is essential for life and plays a crucial role in several biochemical and physiological processes in the human body. Hypomagnesemia is common in all hospitalized patients, especially in critically ill patients with coexisting electrolyte abnormalities. Hypomagnesemia may cause severe and potential fatal complications if not timely diagnosed and properly treated, and associate with increased mortality.Main bodyMg deficiency in critically ill patients is mainly caused by gastrointestinal and/or renal disorders and may lead to secondary hypokalemia and hypocalcemia, and severe neuromuscular and cardiovascular clinical manifestations. Because of the physical distribution of Mg, there are no readily or easy methods to assess Mg status. However, serum Mg and the Mg tolerance test are most widely used. There are limited studies to guide intermittent therapy of Mg deficiency in critically ill patients, but some empirical guidelines exist. Further clinical trials and critical evaluation of empiric Mg replacement strategies is needed.ConclusionPatients at risk of Mg deficiency, with typical biochemical findings or clinical symptoms of hypomagnesemia, should be considered for treatment even with serum Mg within the normal range.

Acute leukemias are a group of aggressive malignant diseases associated with a high degree of morbidity and mortality. An important cause of both the latter is infectious complications. Patients with acute leukemia are highly susceptible to infectious diseases due to factors related to the disease itself, factors attributed to treatment, and specific individual risk factors in each patient. Patients with chemotherapy-induced neutropenia are at particularly high risk, and microbiological agents include viral, bacterial and fungal agents. The etiology is often unknown in infectious complications, although adequate patient evaluation and sampling have diagnostic, prognostic and treatment-related consequences. Bacterial infections include a wide range of potential microbes, both Gram-negative and Gram-positive species, while fungal infections include both mold and yeast. A recurring problem is increasing resistance to antimicrobial agents, and in particular, this applies to extended-spectrum beta-lactamase resistance (ESBL), Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and even carbapenemase-producing Enterobacteriaceae (CPE). International guidelines for the treatment of sepsis in leukemia patients include the use of broad-spectrum Pseudomonas-acting antibiotics. However, one should implant the knowledge of local microbiological epidemiology and resistance conditions in treatment decisions. Here, we discuss infectious diseases in acute leukemia with a major focus on febrile neutropenia and sepsis, and we problematize the diagnostic, prognostic, and therapeutic aspects of infectious complications in this patient group. Meticulously and thorough clinical and radiological examination combined with adequate microbiology samples are cornerstones of the examination. Diagnostic and prognostic evaluation includes patient review according to the multinational association for supportive care in cancer (MASCC) and sequential organ failure assessment (SOFA) scoring system. Antimicrobial treatments for important etiological agents are presented. The main challenge for reducing the spread of resistant microbes is to avoid unnecessary antibiotic treatment, but without giving to narrow treatment to the febrile neutropenic patient that reduce the prognosis.

High titer autoantibodies produced by B lymphocytes are clinically important features of many common autoimmune diseases. APECED patients with deficient autoimmune regulator (AIRE) gene collectively display a broad repertoire of high titer autoantibodies, including some which are pathognomonic for major autoimmune diseases. AIRE deficiency severely reduces thymic expression of gene-products ordinarily restricted to discrete peripheral tissues, and developing T cells reactive to those gene-products are not inactivated during their development. However, the extent of the autoantibody repertoire in APECED and its relation to thymic expression of self-antigens are unclear. We here undertook a broad protein array approach to assess autoantibody repertoire in APECED patients. Our results show that in addition to shared autoantigen reactivities, APECED patients display high inter-individual variation in their autoantigen profiles, which collectively are enriched in evolutionarily conserved, cytosolic and nuclear phosphoproteins. The APECED autoantigens have two major origins; proteins expressed in thymic medullary epithelial cells and proteins expressed in lymphoid cells. These findings support the hypothesis that specific protein properties strongly contribute to the etiology of B cell autoimmunity.

The cytokine network and the adhesion molecule system are intercellular signal pathways. The cytokine effects are modulated in vivo by soluble cytokine antagonists, whereas the cell to cell contact mediated by adhesion molecules and their ligands may be blocked by the soluble forms of the adhesion molecules. The cytokine network is important for proliferation and cytokine secretion by acute leukaemia blasts, and membrane-bound adhesion molecules are important for blast interactions with neighbouring cells of the in vivo microenvironment. Both these signal systems are operative during the period of cytopenia following intensive chemotherapy for acute leukaemia. In the present review, we discuss the influence of disease status, chemotherapy and complicating infections on serum levels of cytokines and soluble adhesion molecules in acute leukaemia patients. We have demonstrated increased serum levels of both cytokines and cytokine antagonists in acute leukaemia patients with complicating bacterial infections during chemotherapy-induced cytopenia. Serum levels of the selectin adhesion molecules were decreased during bacterial infections in leukopenic patients compared to healthy individuals. In contrast, the intercellular adhesion molecule-1 response and the cytokine/cytokine antagonist responses were qualitatively similar to responses seen in previously healthy individuals with serious bacterial infections.

Chronic myelogenous leukemia (CML) is characterized by the t(9;22) translocation that results in chimeric genes encoding bcr/abl fusion proteins. Junction-spanning sequences represent unique tumor-specific moieties that might be exploited therapeutically. We investigate here the binding of synthetic bcr/abl peptides to various HLA-DR alleles and their recognition by T cells from normal donors and CML patients. A 23- mer b3/a2 peptide bound very strongly to isolated HLA-DRB1*1101 (Dw5) and relatively strongly to DRB1*0301 (Dw3) and DRB1*0402 (Dw10) molecules, as estimated using a competition assay. It failed to bind to several other DR alleles, including three different DR4 alleles. In contrast, a 23-mer b2/a2 peptide bound only to the DRB1*0301 (Dw3) allele. Peripheral blood mononuclear cells from normal donors were sensitized in vitro against the b3/a2 peptide. After four repetitive stimulations, T cells responding to the peptide were found at low frequency in 5 of the 11 donors tested. Three of the five were HLA- DR11+, and all three of the DR11+ donors tested were found to respond. T cells recognizing bcr/abl peptides were not identified in any of the CML patients studied, regardless of HLA type. Finally, even peptide- reactive T-cell lines from normal donors were not stimulated by native CML cells in the absence of exogenous peptide. These results show the presence of low-frequency major histocompatability complex class II- restricted bcr/abl-responses in the normal T-cell repertoire of donors with certain HLA types, but suggest that unmodified tumor cells cannot be recognized by such peptide-sensitized T cells.

Both clinical and experimental evidence indicate that T lymphocytes can mediate antileukemic effects in acute myelogenous leukemia (AML). These antileukemic effects can be either nonspecific cytotoxicity (killer cell activity) or reactivity against leukemia-specific antigenic peptides presented by self-HLA molecules. The antigen-specific T cell activation requires recognition of specific peptides together with costimulatory signalling. For most patients the AML blasts express both HLA class I and class II molecules for antigenic presentation, but patients are heterogeneous with regard to: (1) expression of costimulatory binding molecules; (2) expression of receptors/counterreceptors involved in induction of apoptosis; (3) constitutive release of immunomodulatory soluble mediators. This heterogeneity suggests that the ability of AML blasts to initiate an antileukemic T cell response will differ between individual patients. Thus, clinical approaches for immunotherapy in AML have to overcome three major problems. First, the therapy should reduce the patient heterogeneity so that therapeutic effects become more predictable; or alternatively one should define patient subsets which are likely to benefit from immunotherapy. Second, immunotherapy should enhance antileukemic T cell reactivity or blast susceptibility to immune attacks. Third, the therapeutic procedures must be safe and suitable for routine use. All three problems probably have to be solved before immunotherapy can become a routine treatment.