A rare presentation of Legionella pneumophila and Mycobacterium intracellulare co-infection masquerading as metastatic lung cancer in a patient with positive anti-interferon gamma antibody.

Adult-onset immunodeficiency (AOID) syndrome due to the presence of anti-interferon gamma antibody (AIGA) is characterized by multiple opportunistic infections. We report a case of a 65-year old healthy woman who suffered from Legionella pneumophila and Mycobacterium intracellulare co-infection with clinical presentation mimicking metastatic lung cancer. She presented with chronic cough and weight loss. Her positron emission tomography scan showed a right upper lobe mass, mediastinal lymphadenopathy and multiple bone lesions. Acid fast bacilli culture of the lung mass and mediastinal lymph node revealed Mycobacterium intracellulare and she improved with prolonged antibiotic. Relapse of disseminated Mycobacterium intracellulare infection occurred 15 months post-treatment and AIGA was positive with functional neutralizing activity on downstream immune pathway. AOID syndrome secondary to AIGA was diagnosed. This case illustrated the importance of high index of suspicion of AOID syndrome and the difficulty of early diagnosis. Further studies on its predictive factors and AIGA-targeted treatment modalities are urgently needed.

Id proteins: small molecules, mighty regulators.

The family of inhibitor of differentiation (Id) proteins is a group of evolutionarily conserved molecules, which play important regulatory roles in organisms ranging from Drosophila to humans. Id proteins are small polypeptides harboring a helix-loop-helix (HLH) motif, which are best known to mediate dimerization with other basic HLH proteins, primarily E proteins. Because Id proteins do not possess the basic amino acids adjacent to the HLH motif necessary for DNA binding, Id proteins inhibit the function of E protein homodimers, as well as heterodimers between E proteins and tissue-specific bHLH proteins. However, Id proteins have also been shown to have E protein-independent functions. The Id genes are broadly but differentially expressed in a variety of cell types. Transcription of the Id genes is controlled by transcription factors such as C/EBPß and Egr as well as by signaling pathways triggered by different stimuli, which include bone morphogenic proteins, cytokines, and ligands of T cell receptors. In general, Id proteins are capable of inhibiting the differentiation of progenitors of different cell types, promoting cell-cycle progression, delaying cellular senescence, and facilitating cell migration. These properties of Id proteins enable them to play significant roles in stem cell maintenance, vasculogenesis, tumorigenesis and metastasis, the development of the immune system, and energy metabolism. In this review, we intend to highlight the current understanding of the function of Id proteins and discuss gaps in our knowledge about the mechanisms whereby Id proteins exert their diverse effects in multiple cellular processes.

Up-regulation of the Sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) genes in white adipose tissue of Id1 protein-deficient mice: implications in the protection against diet and age-induced glucose intolerance.

Id1, a helix-loop-helix (HLH) protein that inhibits the function of basic HLH E protein transcription factors in lymphoid cells, has been implicated in diet- and age-induced obesity by unknown mechanisms. Here we show that Id1-deficient mice are resistant to a high fat diet- and age-induced obesity, as revealed by reduced weight gain and body fat, increased lipid oxidation, attenuated hepatosteatosis, lower levels of lipid droplets in brown adipose tissue, and smaller white adipocytes after a high fat diet feeding or in aged animals. Id1 deficiency improves glucose tolerance, lowers serum insulin levels, and reduces TNFα gene expression in white adipose tissue. Id1 deficiency also increased expression of Sirtuin 1 and peroxisome proliferator-activated receptor γ coactivator 1α, regulators of mitochondrial biogenesis and energy expenditure, in the white adipose tissue. This effect was accompanied by the elevation of several genes encoding proteins involved in oxidative phosphorylation and fatty acid oxidation, such as cytochrome c, medium-chain acyl-CoA dehydrogenase, and adipocyte protein 2. Moreover, the phenotype for Id1 deficiency was similar to that of mice expressing an E protein dominant-positive construct, ET2, suggesting that the balance between Id and E proteins plays a role in regulating lipid metabolism and insulin sensitivity.

Chronic TLR signaling impairs the long-term repopulating potential of hematopoietic stem cells of wild type but not Id1 deficient mice.

Hematopoietic stem cells (HSCs) maintain life-long blood supply but are inevitably exposed to various inflammatory stimuli, which have been shown to be harmful for HSC integrity but the mediators of the deleterious effects have not been fully identified. Here, we show that daily injection of mice with 1 µg of LPS for 30 days triggers a storm of inflammatory cytokines. LPS injection also stimulated the transcription of the Id1 gene in HSCs in vivo but not in vitro, suggesting an indirect effect. To determine the effects of LPS treatment on HSC function and to evaluate the significance of Id1 expression, we assess the repopulating potential of wild type and Id1 deficient mice, which were subjected to a 30 day regimen of LPS treatment. We found that LPS caused dramatic reduction in the long-term but not short-term repopulating activity of wild type but not Id1 deficient HSC. This treatment also led to increases in HSC counts, decreases in BrdU-label retention and disturbance of quiescence detected by Ki67 staining in wild type but not Id1 deficient mice. Together, it appears that Id1, at least in part, plays a role in LPS-induced damage of HSC integrity.