The present uncertainty of which live viral or bacterial vaccines may be given to immune deficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based upon published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy individuals who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents may occur within the hospital, clinic, home, or at any public gathering. Collectively, we define this type transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who may develop infection when exposed to individuals carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are on immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection, and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable individuals with their social needs to integrate into society, attend school, and benefit from peer education.
The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient and enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP detoxifies adenosine by converting it to inosine (10). The hypotheses then differ in their proposed mechanisms by which adenosine exerts its cytotoxic effects in cells incapable of eliminating this purine nucleoside. It has been proposed that cyclic AMP mediates the cytotoxic effects of adenosine (11,19), that the accumulated nucleotides of adenosine induce a pyrimidine nucleotide starvation (10, 12) or inhibit glycolysis (5), and that adenosine combines intracellularly with homocysteine to form S-adenosylhomocysteine, which in turn acts as a potent inhibitor of methylation reactions, including the methylation of newly synthesized DNA (20).There are specific objections to most of these proposals. In a model system, Ullman et al. (12) We have observed very abnormal levels of 2'-deoxyadenosine triphosphate (dATP) in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent, adenosine deaminase-deficient patient. Furthermore, we have followed the loss of erythrocyte dATP in two unrelated adenosine deaminasedeficient, immunodeficient patients after the infusion of erythrocytes containing the missing enzyme activity.f To whom reprint requests should be addressed
Hormone-sensitive lipase (HSL)1 is an intracellular neutral lipase that is highly expressed in adipose and steroidogenic tissues (1). The enzyme has broad substrate specificity, displaying hydrolytic activity against triacylglycerol, diacylglycerol, and cholesteryl ester (2). Observations from HSL-null mice have shown that HSL is responsible for ϳ50% of the neutral triglyceride lipase activity and all of the neutral cholesteryl ester hydrolase activity in white adipose tissue (3). Thus, HSL plays an important role in regulating lipolysis and the release of fatty acids from adipose tissue. The sequence of HSL is unrelated to other mammalian lipases, but it shares sequence and structural similarity with several bacterial and fungal lipases (4 -11). This structural similarity is based on the ability to model a large portion of the C-terminal ϳ450 amino acids of HSL as an ␣/ hydrolase (7); however, the initial ϳ320 amino acids of the protein share no sequence or structural homology with any known proteins. Within the C-terminal region of the protein lies a 150-amino acid sequence that contains a number of sites phosphorylated in response to lipolytic stimulation (7,12,13). In this regard HSL is unique among lipases for the ability of its activity to be up-regulated by phosphorylation. In addition to phosphorylation, HSL activity appears to be regulated by oligomerization, with the dimeric enzyme exhibiting markedly increased activity (14).Utilizing a yeast two-hybrid screen of a rat adipose tissue library, we previously demonstrated that HSL specifically interacts with adipocyte lipid-binding protein (ALBP or aP2) and identified the N-terminal 300 amino acids of HSL as the region responsible for this interaction (15). ALBP is highly expressed in adipose tissue and is a member of the family of intracellular fatty acid-binding proteins that bind fatty acids, retinoids and other hydrophobic ligands (16). It has been proposed that intracellular fatty acid-binding proteins function to sequester fatty acids, thus serving as an intracellular buffer or participating in facilitating the movement of fatty acids within the cell. In view of our observation that HSL and ALBP interact, we proposed that ALBP might prevent feedback inhibition of HSL by high local concentrations of free fatty acids released at the site of hydrolysis. Consistent with this view, adipocytes from ALBP-null mice exhibit markedly reduced basal and stimulated lipolysis both in situ and in vivo (17,18). In the present studies we have addressed the functional significance of the interaction of HSL with ALBP and provide evidence that the interaction of ALBP with HSL constitutes an additional mechanism whereby the hydrolytic activity of HSL is regulated. Furthermore, we have explored the identification of the sequences in HSL that mediate its interaction with ALBP.
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