RAC2 and primary human immune deficiencies Lougaris, Vassilios; Baronio, Manuela; Gazzurelli, Luisa ...
Journal of leukocyte biology,
August 2020, Letnik:
108, Številka:
2
Journal Article
Recenzirano
RAC2 is a GTPase that is exclusively expressed in hematopoietic cells. Animal models have suggested important roles for RAC2 in the biology of different cell types, such as neutrophils and ...lymphocytes. Primary immunodeficiencies represent “experimentum naturae” and offer priceless insight on the function of the human immune system. Mutations in RAC2 have been identified in a small number of patients giving rise to different forms of primary immunodeficiencies ranging from granulocyte defects caused by dominant negative mutations to combined immunodeficiency due to dominant activating mutations. This review will focus on the clinical and immunologic phenotype of patients with germline mutations in RAC2.
Germline Rac2 mutations result in variable clinical and immunological presentation in patients with primary immune deficiencies
Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the ...first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients’ clinical management and their quality of life.
X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.
Our aim was to ...describe the natural history of XLA.
A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients’ laboratory, clinical, and imaging data were recorded on an annual base.
Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease.
This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients’ clinical management and increase awareness among physicians.
This study provides evidence for the first time for APDS-1 presenting as MAS/HLH, with evident clinical implications in patient's management and prognosis.
•APDS-1 may present with MAS/HLH ...features.•MAS/HLH of undefined aetiology may benefit from additional immunological and functional evaluation.
Cyclosporin A (CsA) is used in the treatment of patients undergoing renal transplantation. There are a number of side effects associated with its use. In particular, the gingival overgrowth ...represents the most important in the oral cavity. The authors present a case of bilateral mandibular cysts in an 8-year-old boy, treated with CsA after renal transplantation. The genesis of the mandibular cysts might be associated with the combined use of CsA and a calcium channel blocker post-transplantation. CsA-induced gingival overgrowth might contribute to cysts by two mechanisms: interference with control mechanisms that regulate the reabsorption of gingival stromal tissue, allowing progressive dental eruption, and an increase in the gingival connective tissue components. Gingival hypertrophy might mechanically obstruct the eruption of the developing tooth.
Autism Spectrum Disorder (ASD) is a complex condition with early childhood onset, characterized by a set of common behavioral features. The etiology of ASD is not yet fully understood; however, it ...reflects the interaction between genetics and environment. While genetics is now a well-established risk factor, several data support a contribution of the environment as well. This paper summarizes the conclusions of a consensus conference focused on the potential pathogenetic role of environmental factors and on their interactions with genetics. Several environmental factors have been discussed in terms of ASD risk, namely advanced parental age, assisted reproductive technologies, nutritional factors, maternal infections and diseases, environmental chemicals and toxicants, and medications, as well as some other conditions. The analysis focused on their specific impact on three biologically relevant time windows for brain development: the periconception, prenatal, and early postnatal periods. Possible protective factors that might prevent or modify an ASD trajectory have been explored as well. Recommendations for clinicians to reduce ASD risk or its severity have been proposed. Developments in molecular biology and big data approaches, which are able to assess a large number of coexisting factors, are offering new opportunities to disentangle the gene⁻environment interplay that can lead to the development of ASD.
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt ...upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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