molecules Review Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID Giuliana Amato 1, Federica Vita 1, Paolina Quattrocchi 1, Paola Lucia Minciullo 1, Giovanni Pioggia 2,* and Sebastiano Gangemi 1 1 Operative Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (G.A.); [email protected] (F.V.); [email protected] (P.Q.); [email protected] (P.L.M.); [email protected] (S.G.) 2 Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy * Correspondence: [email protected] Received: 21 August 2020; Accepted: 14 October 2020; Published: 16 October 2020 Abstract: Background and objectives: Common variable immunodeficiency (CVID) is the most prevalent antibody impairment. It is characterized by failure in immunoglobulin and protective antibody generation and defined by an increased tendency toward bacterial infections, autoimmunity, and malignancy. Most CVID diagnoses do not follow a classical Mendelian pattern of inheritance. In recent years, CVID has been considered an epigenetic phenomenon in the majority of cases, overtaking previous monogenetic and/or polygenetic theories. The aim of this study was to review the role of microRNAs (miRNAs) in CVID, focusing on the involvement of the same miRNAs in various non-infectious clinical complications of CVID, mainly autoimmunity and/or cancer. Materials and Methods: A bibliographic search of the scientific literature was carried out independently by two researchers in scientific databases and search engines. The MeSH terms “microRNAs” and “common variable immunodeficiency” were used. All research articles from inception to May 2020 were considered. Results: The literature data showed the involvement of two miRNAs in primary immunodeficiency: miR-142 and miR-155. Both of these miRNAs have been investigated through mice models, in which miR-142 and miR-155 were deleted. These knock-out (KO) mice models showed phenotypic analogies to CVID patients with hypogammaglobulinemia, adaptive immunodeficiency, polyclonal proliferation, lung disease, and enteric inflammation. miR-142 and miR-155 have been found to be involved in the following autoimmune and neoplastic clinical complications of CVID: Gastric cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, natural killer/Tcell lymphoma (NKTCL), and immune thrombocytopenia. Conclusions: miR-142 and miR-155 deregulation leads to similar CVID phenotypesin KO mice models. Although no data are available on the involvement of these miRNAs in human CVID, their dysregulation has been detected in human CVID comorbidities. The literature data show that miRNA sequences in murine models are comparable to those in humans; therefore, miR-142 and miR-155 involvement in human CVID could be hypothesized. Keywords: common variable immunodeficiency; microRNAs; miR-142; miR-155; autoimmunity; cancer 1. Introduction Common variable immunodeficiency (CVID) is the most prevalent antibody impairment, characterized by failure in immunoglobulin and protective antibody generation, defined by an Molecules 2020, 25, 4760; doi:10.3390/molecules25204760 www.mdpi.com/journal/molecules Molecules 2020, 25, 4760 2 of 10 Molecules 2020, 25, 4760 2 of 10 increasedinfectious complications tendency toward (Figure bacterial 1), autoimmune infections, diseases autoimmunity, develop andin 20–30% malignancy. of subjects; Among immune the non-infectiousthrombocytopenia complications purpura (ITP) (Figure and1), autoimmune diseaseshemolyticanemia develop in are 20–30% the most of subjects; common, immune while thrombocytopeniaother autoimmune purpura features (ITP) include and autoimmune inflammatory hemolyticanemia bowel disease, are theantiphospholipid most common, whilesyndrome, other autoimmune featuresthyroiditis, include uveitis, inflammatory primary bowelbiliary disease, cirrhosis, antiphospholipid vasculitis, and syndrome, joint manifestations autoimmune thyroiditis,resembling uveitis,rheumatoid primary arthritis. biliary Regarding cirrhosis, vasculitis, malignancy, and gastric joint manifestations cancer and lymphoma resembling are rheumatoid the most arthritis.frequent findings; Regarding in particular, malignancy, most gastric lymphoma cancers are and Bcell-type lymphoma non-Hodgkin are the most lymphoma frequent and findings; some inof particular,these could most be associated lymphomas with are mucosa-assoc Bcell-type non-Hodgkiniated lymphoid lymphoma tissue (MALT). and some Hodgkin of these lymphoma, could be associatedchronic myeloid with mucosa-associated leukemia, thyroid lymphoidpapillary carcinoma, tissue (MALT). and Hodgkinpancreatic lymphoma, neuroendocrine chronic carcinoma myeloid leukemia,have also thyroidbeen described papillary [1,2]. carcinoma, Most diagnoses and pancreatic do not neuroendocrine follow a classical carcinoma Mendelian have pattern also been of describedinheritance. [1 ,In2]. recent Most diagnosesyears, CVID do has not been follow considered a classical an Mendelian epigenetic pattern phenomenon of inheritance. in the majority In recent of years,cases, overtaking CVID has beenprevious considered monoge annetic epigenetic and/or polygenetic phenomenon theories. in the Epigenetics majority of results cases, overtakingin changes previousin gene expression, monogenetic without and/or modifying polygenetic the theories. germ-line Epigenetics DNA gene results sequences. in changes Epigenetic in gene mechanisms expression, withoutare influenced modifying by various the germ-line factors, DNA such gene as infectious, sequences. environmental, Epigenetic mechanisms nutritional, are and influenced iatrogenic by variousstimuli, factors,and include such asDNA infectious, methylation, environmental, cell-specific nutritional, transcription and iatrogenicfactor expression, stimuli, andhistone include and DNAchromatin methylation, modification, cell-specific and non- transcriptioncoding RNAs. factor expression,Early hematopoietic histone and stemcell chromatin differentiation modification, is andsusceptible non-coding to epigenetic RNAs. Earlyprocesses, hematopoietic particular stemcellly DNA dihypomethylationfferentiation is susceptiblemyeloid (as to opposed epigenetic to processes,lymphoid) particularly lineage engagement. DNA hypomethylation myeloid (as opposed to lymphoid) lineage engagement. Figure 1.1. Non-infectiousNon-infectious complications complications of of common common variable variable immunodeficiency immunodeficiency (CVID). (CVID). MALT, MALT, mucosa-associated lymphoid tissue; NK,NK, naturalnatural killer.killer. microRNAs (miRNAs) are small single-stranded non-coding RNA molecules that epigenetically regulate gene expression,expression, mainlymainly throughthrough bindingbinding toto thethe 330′ untranslateduntranslated region (3(30′-UTR) of targeted messenger RNA (mRNA) molecules and, thus, mediating translational repression, commonly along with mRNA degradation. The activity and function of key signaling pathways and cellular processes such as cellcell didifferentiation,fferentiation, proliferation, apoptosis, and response to hypoxia are controlled by a thousand didifferentfferent miRNAs,miRNAs, administeringadministering almostalmost 60%60% ofof thethe protein-codingprotein-coding genesgenes [[3].3]. The aimaim ofof thisthis studystudy waswas to to review review the the role role of of miRNAs miRNAs in in CVID, CVID, focusing focusing on on the the involvement involvement of theof the same same miRNAs miRNAs in in various various non-infectious non-infectious clinical clinical complications complications of of CVID,CVID, mainlymainly autoimmunityautoimmunity andand/or/or cancer.cancer. 2. Materials and Methods A bibliographic search of the scientific literature was carried out in scientific databases and search engines independently by two researchers. The MeSH terms “microRNAs” and “common Molecules 2020, 25, 4760 3 of 10 2. Materials and Methods Molecules 2020, 25, 4760 3 of 10 A bibliographic search of the scientific literature was carried out in scientific databases and search variableengines independentlyimmunodeficiency” by two were researchers. used. All The resear MeSHch termsarticles “microRNAs” from inception and to “common May 2020 variable were considered.immunodeficiency” were used. All research articles from inception to May 2020 were considered. 3.3. Results Results TheThe literature literature data data show show the the involvement involvement of two of twomiRNAs miRNAs in primary in primary immunodeficiency: immunodeficiency: miR- 142miR-142 [4] and [4 ]miR-155 and miR-155 [5]. Both [5]. of Both these of miRNAs these miRNAs have been have investigated been investigated through through mice models mice models in which in miR-142which miR-142 and miR-155 and miR-155 were weredeleted. deleted. These These knoc knock-outk-out (KO) (KO) mice mice models models showed showed phenotypic analogiesanalogies to to CVID patients with hypogammaglobulinemia, adaptive adaptive immunodeficiency, immunodeficiency, polyclonal proliferation, lung lung disease, disease, and and enteric enteric inflammation inflammation [6]. [6 ].Although Although miR-142 miR-142 and and miR-155 miR-155 deletion deletion in CVIDin CVID patients patients has has not not been been detected detected yet, yet, both both of these of these miRNAs miRNAs have have been been found found to be to beinvolved involved in thein the following following