Fig 1 - uploaded by John B Ziegler
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X-ray at age 3 months. Note clouded lung fields, absent thymic shadow, andflared anterior ends of ribs.
Source publication
A first-born baby boy presented at age 3 months with persistent diarrhoea, failure to thrive, and recurrent bacterial and fungal infections. Severe combined immunodeficiency was demonstrated. A deficiency of adenosine deaminase (ADA) activity was suggested by the presence of extensive skeletal abnormalities, and the ADA activity in erythrocyte and...
Citations
... 89 On the other hand, with COVID-19 as with pandemic influenza, the majority of the population do not suffer major deleterious infection, with only a small percentage being more severely impacted. For influenza, individual susceptibility is only recently beginning to be understood 26,27,90 ; however, we now have an explanation for susceptibility to COVID-19 in 15-20% of individuals who suffer severe disease, with the virus seeming less likely to affect the average humans, or even humans with common variation, but rather those with rare, highly deleterious, genetic or immune variation. [13][14][15]55 In effect, we as a species appear to have reasonable innate resistance to the effects of SARS-CoV-2, presumably because of previously having had our genomes put under pressure by similar viruses, resulting in the evolution of a protective type I IFN response among other features of innate immunity. ...
Since the emergence of the COVID-19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre-existing comorbidities, that predispose some people to severe disease, while many other SARS-CoV-2-infected individuals experience mild, if any, consequences. One explanation for intra-individual differences in susceptibility to severe COVID-19 may be that a growing percentage of otherwise healthy people have a pre-existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS-CoV-2 infection. Germline genetic defects have been identified in individuals with life-threatening COVID-19 that compromise local type I interferon (IFN)-mediated innate immune responses to SARS-CoV-2. Remarkably, these variants - which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines - may account for between 3% and 5% of severe COVID-19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN-α, IFN-ω) have been detected in patients' serum prior to infection with SARS-CoV-2 and were found to cause c. 20% of severe COVID-19 in the above 70s and 20% of total COVID-19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID-19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN-α or IFN-β, and may facilitate better management of social distancing, vaccination and early post-exposure prophylaxis.
A biphasic increase in surface hydrophobicity of the surfactant-biodegrading bacterium Pseudomonas C12B has been correlated with biodegradation of the primary alkyl sulphate, sodium dodecyl sulphate. Using both hydrophobic interaction chromatography and microbial adhesion to hydrocarbon to measure surface hydrophobicity, it was shown that the first phase coincides with production of the primary metabolite dodecan-1-ol. The direct addition of dodecan-1-ol to Pseudomonas C12B resulted in the instantaneous increase in surface hydrophobicity, with a subsequent decrease which coincided with dodecan-1-ol biodegradation. In contrast, incubation of Pseudomonas C12B with sodium dodecane sulphonate, a non-metabolizable surfactant analogue of SDS, or the growth-supporting carbon source sodium pyruvate did not alter the surface hydrophobicity. These data are interpreted in terms of a model in which the hydrophobic metabolite dodecan-1-ol enters the bacterial membranes, thus increasing surface hydrophobicity and that these surfactant-biodegradation-dependent changes in bacterial surface hydrophobicity are correlated with reversible attachment of the bacteria to sediment surfaces.
1. Deoxyadenosine metabolism was compared in intact erythrocytes from two children with severe combined immunodeficiency: one had normal adenosine deaminase (ADA; EC 3.5.Lt.4) levels and the other, a homozygote for ADA deficiency, had (following a bone-marrow graft) 15% of normal activity in lysed erythrocytes.
The most severe, and also a relatively common immunodeficiency syndrome involves both antibody- and cell-mediated immune mechanisms. In more modern terms the ‘severe combined immunodeficiency’ syndromes (SCID) are defined as all diseases resulting from marked and longlasting functional impairment of both the T- and B-cell system. Accordingly, the clinical symptoms and signs involve many organs and invariably lead to death. An almost constant feature is thymic dysplasia.
During the past decade knowledge of the events of cellular maturation and of regulatory cellular interactions involved in the normal immune response has expanded rapidly as a result of the interplay between studies of patients with primary immunodeficiency diseases and basic laboratory studies in animal systems. Progress in our understanding of disorders of T cell function in immunodeficiency diseases has been facilitated by advances in a number of areas including: 1) The demonstration that T cells are not a homogeneous population but encompass subpopulations of lymphocytes with different and at times opposing functions; 2) The identification of unique cell surface determinants on mouse T cells and more recently on human T cells that appear as these cells mature and differentiate. In many cases T cell subpopulations with different functional capabilities bear different surface determinants; 3) The development of in vitro techniques to assess the functional behavior of isolated subpopulations of T cells and for the evaluation of T cell function in man.
Primary immunodeficiency disorders have traditionally been classified as to whether the cellular, the humoral or both arms of the immune system are affected [10]. The recent discovery of three, [42, 43, 66] and possibly four [28] specific inherited molecular defects which give rise to immunodeficiency syndromes, provides a further basis for diagnosis, classification and delineation of primary immune disorders. Thus, inherited absence of adenosine deaminase (ADA) usually gives rise to the clinical syndrome of severe combined immunodeficiency, purine nucleoside phosphorylase deficiency to a cellular immune deficiency syndrome and absence of transcobalamin II to agammaglobulinemia, as well as defects of other hematopoietic stem cells. Finally, diminished activity of 5′ nucleotidase has been found associated with hypogammaglobulinemia [28, 70]. The finding of specific molecular defects also provides tools for further insight into the differentiation and interaction of the components of the immune system, the metabolic pathways involved and potentially for development of selective immunosuppressive agents and for metabolic manipulation of abnormalities of the immune response.
Rabbit antibody to calf adenosine deaminase (ADA) was used to localize this enzyme in tissues of the young rat and calf by the immunoperoxidase method. The distribution patterns of ADA in most tissues were similar for both species. Within the thymus gland, the enzyme was strongly expressed predominantly in cortical lymphocytes. In the spleen and lymph nodes, most lymphocytes of T-cell areas stained weakly for ADA, whereas only a small number of ADA-positive cells were found in B-cell areas. Clumps of strongly ADA-positive mononuclear blastoid and plasma cells were observed in the medullary regions of lymph nodes, around peri-arteriolar lymphocyte sheaths and in the red pulp of the spleen, and in the lamina propria of the intestine. Double immunofluorescence staining studies in the rat showed that some of these blastoid cells contained both ADA and immunoglobulins and appeared to be plasmablasts. Strong staining for ADA was also found, in both the rat and calf, in as yet unidentified mononuclear blastoid cells in the interstitium of non-lymphoid organs (kidney, heart, lung), in endothelial cells of some arterioles and capillaries, and in Kupffer cells of the liver. In addition, ADA was strongly expressed in calf bile canaliculi. These studies define areas in rat and calf tissues which contain ADA-positive cells and provide a model system for investigations of the relationship between ADA and the function and development of these cells.
1. Adenosine inhibits thymidine and uridine incorporation of PHA-stimulated lymphocytes of man and horse at concentrations higher than 50 and 10 microM, respectively. Deoxyadenosine is inhibitory at concentrations higher than 100 microM. Thymidine and uridine incorporation of porcine lymphocytes are elevated 5-7-fold by 25-100 microM adenosine, deoxyadenosine, inosine and hypoxanthine. Leucine incorporation of PHA-stimulated lymphocytes was affected by adenosine and deoxyadenosine in the same way, but to a lower extent. 2. Effects of adenosine and deoxyadenosine were more pronounced at shorter cultivation times. 3. EHNA potentiated the effects of adenosine and deoxyadenosine on human and equine lymphocytes. With human lymphocytes inhibition by deoxyadenosine and EHNA was higher than by adenosine and EHNA. With porcine lymphocytes only the combination of deoxyadenosine and EHNA was inhibitory. 4. Homocysteine potentiated the inhibition of thymidine incorporation by the combination of adenosine and deoxyadenosine with equine lymphocytes, but not the inhibition of adenosine or deoxyadenosine alone. 5. Adenosine suppressed the PHA-stimulated elevation of PRPP concentrations. With porcine lymphocytes PRPP remained at the level of 0 hr, while with equine lymphocytes PRPP concentration decreased to below that level. 6. The various effects of adenosine and deoxyadenosine on lymphocytes of man, horse and pig can partially be related to differences in adenosine and deoxyadenosine metabolism.
To evaluate the importance of altered pyrimidine synthesis in the relationship between immune dysfunction and deficiency of ADA, this pathway has been evaluated in normal and ADA-deficient human lymphoblasts. Adenosine and deoxyadenosine effect comparable reductions of radiolabeled bicarbonate incorporation in uridine nucleosides of both normal and deficient cells, with this effect being more prolonged in deficient cells. In ADA-deficient lymphoblasts this altered pyrimidine metabolism is accompanied by reduced intracellular concentrations of PP-ribose-P with adenosine but not deoxyadenosine. The altered PP-ribose-P levels are accompanied by orotic acid accumulation, but this block does not fully account for the net reduction in uridine nucleotide synthesis. This suggests interference of the pyrimidine pathway at another locus, possibly by altered carbamyl phosphate synthetase activity. The mechanism for deoxyadenosine-mediated inhibition is obscure. Despite the demonstrable adenosine- and deoxyadenosine-mediated alterations of pyrimidine metabolism, these changes are not accompanied by marked interference of cell growth for both normal and ADA-deficient lymphoblasts. These data support the hypothesis that altered pyrimidine metabolism is not the basis for the immune disorder in patients with deficiency of ADA.
