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Background Granulomatous and lymphocytic interstitial lung disease (GLILD) is a life-threatening complication in patients with common variable immunodeficiency (CVID), but the optimal treatment is unknown. Objective Our aim was to determine whether rituximab with azathioprine or mycophenolate mofetil improves the high-resolution computed tomography (HRCT) chest scans and/or pulmonary function test results in patients with CVID and GLILD. Methods A retrospective chart review of clinical and laboratory data on 39 patients with CVID and GLILD who completed immunosuppressive therapy was performed. Chest HRCT scans, performed before therapy and after the conclusion of therapy, were blinded, randomized, and scored independently by 2 radiologists. Differences between pretreatment and posttreatment HRCT scan scores, pulmonary function test results, and lymphocyte subsets were analyzed. Whole exome sequencing was performed on all patients. Results Immunosuppressive therapy improved patients' HRCT scan scores (P Conclusions Immunosuppressive therapy improved the radiographic abnormalities and pulmonary function of patients with GLILD. A majority of patients had sustained remissions.

The specific antibody response to the unconjugated 23-valent pneumococcal polysaccharide vaccine is one of the most common tests used to assess for possible humoral immunodeficiency. The results can be difficult to interpret because most people have been immunized with one or more of the pneumococcal vaccines and there is controversy regarding what constitutes a normal response. To circumvent this problem, we developed an ELISA to measure IgG-specific antibodies to the Salmonella Vi Typhim (S. Typhim) vaccine, a pure polysaccharide vaccine, which is a neoantigen for the vast majority of people in the USA. We compared the pre- and post-vaccination serum titers to the Vi Typhim vaccine in healthy controls (n = 22), patients previously diagnosed with a primary immunodeficiency (n = 30), and patients referred for possible humoral immune deficiency (n = 29). We also determined if the S. Typhim vaccine could be used to assess specific antibody responses in people on antibody replacement therapy. Following immunization with the S. Typhim vaccine, we found that a 2-fold increase in titers is 100% sensitive and specific in detecting known humoral immune deficiencies as determined by ROC curve analysis. This cut-off value was successfully applied to possible immune deficiency patients (n = 29), resulting in the diagnosis of seven subjects with humoral immunodeficiency. The use of immunoglobulin replacement therapy did not affect the median response ratios compared to subjects not receiving gammaglobulin. This study suggests that measurement of the specific antibody response to the S. Typhim vaccine may have advantages over pneumococcal vaccination in the evaluation of the humoral immune response.

Chapter 8 reviews the disease burden of traditional risk factors (hypertension, dyslipidemia, obesity, diabetes, diet, and smoking), as well as emerging risks (pollution, sleep apnea, chronic obstructive pulmonary disease and psychosocial stress). In each instance, vascular injury is associated with inflammation and oxidative stress. The role of autonomic imbalance in this process is also considered. An understanding of the pathophysiology of the vascular injury may suggest new targets for drug therapy for cardiovascular disease prevention.

Human AMPD2 cDNA clones have been isolated from T-lymphoblast and placental lambda gt11 libraries utilizing a previously cloned rat partial AMPD2 cDNA as the probe. Alignment analysis of all cDNA clones indicates the presence of intervening sequences in several placental isolates. This has been confirmed by sequencing human AMPD2 genomic clones. Intervening sequences can be removed from the cDNA clones by restriction with endonucleases at unique sites within the proposed open reading frame. This results in a 3292-base pair cDNA proposed to contain the entire AMPD2 open reading frame, which would encode a 760-amino acid polypeptide with a predicted subunit molecular mass of 88.1 kDa. Nucleotide and predicted amino acid comparisons with the 264 base pairs of proposed coding sequences in the rat AMPD2 cDNA demonstrate 91% similarity and identity, respectively. A comparison of the predicted human AMPD1 and AMPD2 polypeptides demonstrates homology in their C-terminal domains. Included in this region is the conserved motif, SLSTDDP, proposed to be part of the catalytic site of all AMP deaminases. In contrast, the predicted N-terminal domains of the human AMPD1 and AMPD2 polypeptides are unique. When placed in a prokaryotic expression vector, the human AMPD2 cDNA expresses AMP deaminase activity which can be precipitated with polyclonal antisera specific for isoform L.

AMP deaminase (AMPD) is manifest through a multigene family in higher eukaryotes, including man. The human AMPD1 and AMPD3 genes have been cloned and partially characterized. This study describes the cloning, chromosomal localization, partial-sequence and characterization of the human AMPD2 gene. Composed of nineteen exons and eighteen intervening sequences spanning nearly 14 kb of genomic DNA, the human AMPD2 gene is positioned on the short arm of chromosome 1 near the p13.3 boundary. Two alternative 5′ exons (1A and 1B) are remotely located upstream, whereas the other seventeen are compressed into the 3′ terminal one-half of the gene. Transient transfections of human retinal pigment epithelial (RPE) cells using heterologous constructs containing 5′ flanking and 5′ untranslated sequences cloned upstream of a luciferase reporter gene show that promoter activities are associated with exons 1A and 1B. Inspection of genomic DNA sequence reveals that AMPD2 promoter regions lack readily identifiable TATA boxes and are G + C-rich, particularly in the region of multiple transcription initiation sites in exon 1A. The regulation and evolution of the entire human AMPD multigene family are discussed.

Adenosine monophosphate (AMP) deaminase is a purine nucleotide interconverting enzymatic activity critical to energy metabolism, e.g., its role in the proposed functions of the purine nucleotide cycle (Lowenstein 1972). In higher eukaryotes, multiple isoforms exhibiting tissue-specific and developmental patterns of expression have been described. In addition to exhibiting diverse biochemical and immunological properties, limited cellular biology studies suggest that intraspecies variants of AMP deaminase occupy different intracellular addresses. Recent molecular studies have demonstrated AMP deaminase isoforms to be manifest through the expression of a multigene family, some members of which produce primary transcripts subject to alternative splicing. Clinically, inherited and acquired deficiencies of skeletal muscle AMP deaminase (Sabina et al. 1989b) and an inherited deficiency in erythrocytes (Ogasawara et al. 1984b) have been described. Our laboratory is utilizing cellular and molecular approaches to gain insight into the functional significance of AMP deaminase isoform diversity.