Advances in basic and clinical immunology in 2016
2017; Elsevier BV; Volume: 140; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2017.07.023
ISSN1097-6825
AutoresJavier Chinen, Yousef R. Badran, Raif S. Geha, Janet Chou, Ari J. Fried,
Tópico(s)Immune Cell Function and Interaction
ResumoAdvances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T and B cells, including cytokines and proteins involved in the actin cytoskeleton. Regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohistiocytosis. The role of prenylation in patients with mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology, as well as new approaches of whole-genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT); B-cell CLL/lymphoma 11B (BCL11B); RGD, leucine-rich repeat, tropomodulin domain, and proline-rich domain–containing protein (RLTPR); moesin; and Janus kinase 1 (JAK1). Trials of hematopoietic stem cell transplantation and gene therapy for primary immunodeficiency have had relative success; the use of autologous virus-specific cytotoxic T cells has proved effective as well. New medications are being explored, such as pioglitazone, which is under study for its role in enhancing the oxidative burst in patients with chronic granulomatous disease. Development of vaccines for HIV infection continues to provide insight into the immune response against a virus with an extraordinary mutation rate. Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T and B cells, including cytokines and proteins involved in the actin cytoskeleton. Regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohistiocytosis. The role of prenylation in patients with mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology, as well as new approaches of whole-genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT); B-cell CLL/lymphoma 11B (BCL11B); RGD, leucine-rich repeat, tropomodulin domain, and proline-rich domain–containing protein (RLTPR); moesin; and Janus kinase 1 (JAK1). Trials of hematopoietic stem cell transplantation and gene therapy for primary immunodeficiency have had relative success; the use of autologous virus-specific cytotoxic T cells has proved effective as well. New medications are being explored, such as pioglitazone, which is under study for its role in enhancing the oxidative burst in patients with chronic granulomatous disease. Development of vaccines for HIV infection continues to provide insight into the immune response against a virus with an extraordinary mutation rate. New research developments in basic and clinical immunology continue to expand the number of immune mechanisms and explain the clinical manifestations resulting from impairment of the immune response. We present selected articles describing progress in basic and clinical immunology that were published in the scientific literature in 2016, with emphasis on themes related to immunodeficiency. T cells play a central role in cell-mediated immunity. Development of T cells in the thymus, their differentiation into different subpopulations, interaction with other cells involved in an immune response, and signaling downstream of surface receptors are all key aspects of understanding T-cell function in health and disease. Wiekmeijer et al1Wiekmeijer A.S. Pike-Overzet K. IJspeert H. Brugman M.H. Wolvers-Tettero I.L. Lankester A.C. et al.Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells.J Allergy Clin Immunol. 2016; 137: 517-526Abstract Full Text Full Text PDF PubMed Google Scholar studied thymic T-cell development using a xenograft mouse model in which NOD-Scid-Il2rg−/− mice underwent transplantation with CD34+ stem cells isolated from patients with severe combined immunodeficiency (SCID) caused by different gene defects. The authors showed that common γ chain cytokine signaling is required almost immediately after T-cell progenitors seed the thymus because deleterious mutations in IL2RG, encoding IL-2 receptor γ, and IL7RA, encoding IL-7 receptor α, block T-cell development at the CD4−CD8−CD7−CD5− and CD4−CD8−CD7+CD5− double-negative (DN) stages, respectively (Table I).1Wiekmeijer A.S. Pike-Overzet K. IJspeert H. Brugman M.H. Wolvers-Tettero I.L. Lankester A.C. et al.Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells.J Allergy Clin Immunol. 2016; 137: 517-526Abstract Full Text Full Text PDF PubMed Google Scholar, 2Brauer P.M. Pessach I.M. Clarke E. Rowe J.H. Ott de Bruin L. Lee Y.N. et al.Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies.Blood. 2016; 128: 783-793Crossref PubMed Scopus (2) Google Scholar Artemis-deficient cells stop developing at the CD4−CD8−CD7+CD5+ DN stage, demonstrating the importance of T-cell receptor (TCR) rearrangements at this stage.Table IArrest in human T-cell development caused by SCID gene defects using 2 different experimental modelsGeneT-cell developmental arrestTCRD locus rearrangementMethodADANormal developmentNormalXenograft mouse modelArtemisCD4−CD8−CD7+CD5+ DN stageBroad repertoire TCRDδ2-Dδ3No rearrangement TCRG, TCHRBXenograft mouse modelIL7RACD4−CD8−CD7+CD5− DN stageNo rearrangementXenograft mouse modelIL2RGCD4−CD8−CD7−CD5− DN stageNo rearrangementXenograft mouse modelIL2RG hypomorphicNormal development, decreased T-cell numbersNot doneXenograft mouse modelRAG1CD4−CD8−CD7+CD5+ CD38−CD31−/loCD45RA+DN stageNo rearrangementiPSCNormal development of adenosine deaminase–deficient T cells results from exogenous mouse adenosine deaminase (Wiekmeijer et al1Wiekmeijer A.S. Pike-Overzet K. IJspeert H. Brugman M.H. Wolvers-Tettero I.L. Lankester A.C. et al.Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells.J Allergy Clin Immunol. 2016; 137: 517-526Abstract Full Text Full Text PDF PubMed Google Scholar and Brauer et al2Brauer P.M. Pessach I.M. Clarke E. Rowe J.H. Ott de Bruin L. Lee Y.N. et al.Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies.Blood. 2016; 128: 783-793Crossref PubMed Scopus (2) Google Scholar). Open table in a new tab Normal development of adenosine deaminase–deficient T cells results from exogenous mouse adenosine deaminase (Wiekmeijer et al1Wiekmeijer A.S. Pike-Overzet K. IJspeert H. Brugman M.H. Wolvers-Tettero I.L. Lankester A.C. et al.Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells.J Allergy Clin Immunol. 2016; 137: 517-526Abstract Full Text Full Text PDF PubMed Google Scholar and Brauer et al2Brauer P.M. Pessach I.M. Clarke E. Rowe J.H. Ott de Bruin L. Lee Y.N. et al.Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies.Blood. 2016; 128: 783-793Crossref PubMed Scopus (2) Google Scholar). An alternative approach for studying T-cell development using samples from patients with SCID was reported by Brauer et al.2Brauer P.M. Pessach I.M. Clarke E. Rowe J.H. Ott de Bruin L. Lee Y.N. et al.Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies.Blood. 2016; 128: 783-793Crossref PubMed Scopus (2) Google Scholar They generated induced pluripotent stem cells (iPSCs) using dermal fibroblasts from patients with recombination-activating gene 1 (RAG1) mutations differentiated in vitro into CD34+ cells and then into T cells. The differentiated cells had a block at the CD4−CD8−CD7+CD5+CD38−CD31−/loCD45RA+ stage, even those obtained from patients with Omenn syndrome (OS), who had residual RAG1 recombination activity. This was attributed to accumulation of single-strand DNA breaks in cells from patients with OS, resulting in impaired cell survival and differentiation. CD4+ single-positive and CD4+ CD8+ double-positive T-cell precursors generated in vitro from iPSCs from patients with OS and those with SCID had comparable severe restriction in repertoire diversity. Resop et al3Resop R.S. Douaisi M. Craft J. Jachimowski L.C. Blom B. Uittenbogaart C.H. Sphingosine-1-phosphate/sphingosine-1-phosphate receptor 1 signaling is required for migration of naive human T cells from the thymus to the periphery.J Allergy Clin Immunol. 2016; 138: 551-557Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar demonstrated that expression of sphingosine-1-phosphate (S1P) receptor 1 on mature thymocytes is essential for their egress from the thymus. Using in vitro transwell migration assays, the authors showed that mature CD3hiCD27+CD45RA+CD62L+CD69− thymocytes had the greatest migration toward S1P and that thymocytes downregulate S1P receptor 1 on interaction with S1P. The investigators also suggested a role for S1P receptor 2 in thymocyte retention in the thymus. Modulation of the interaction between S1P and its receptor was proposed as a potential strategy for increasing T-cell counts in primary immunodeficiencies (PIDs) characterized by impaired T-cell egress. On thymic egress, T cells undergo a short period of postthymic maturation in the periphery, which has now been shown to be important for tolerance induction to tissue-restricted antigens.4Friesen T.J. Ji Q. Fink P.J. Recent thymic emigrants are tolerized in the absence of inflammation.J Exp Med. 2016; 213: 913-920Crossref PubMed Scopus (12) Google Scholar The outcome of this T-cell interaction with tissue-restricted antigens is determined by the context of the interaction: in the absence of inflammation, recent thymic emigrants are tolerized; in the presence of inflammation, recent thymic emigrants are directed toward effector cell differentiation in which mature T cells contribute to autoimmune disease. The ability of naive CD4+ T cells to differentiate into effector populations in vitro was studied in patients with different PIDs.5Ma C.S. Wong N. Rao G. Nguyen A. Avery D.T. Payne K. et al.Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.J Exp Med. 2016; 213: 1589-1608Crossref PubMed Google Scholar IL-12 receptor β1/TYK2 and IFN-γ receptor/signal transducer and activator of transcription (STAT) 1 signaling were demonstrated to be important for induction of TH1 cells, and IL-21/IL-21 receptor/STAT3 signaling was demonstrated to be important for induction of TH17, follicular helper T (TFH), and IL-10–secreting cells. Signaling by IL-12 receptor β1/TYK2 and nuclear factor κB (NF-κB) essential modulator were also proved to be necessary for TH17 induction. The authors showed that hyperactivation of STAT1 inhibits STAT3 signaling by showing that gain-of-function STAT1 and dominant-negative STAT3 mutations had a similar effect on TFH and TH17 cells. Noster et al6Noster R. de Koning H.D. Maier E. Prelog M. Lainka E. Zielinski C.E. Dysregulation of proinflammatory versus anti-inflammatory human TH17 cell functionalities in the autoinflammatory Schnitzler syndrome.J Allergy Clin Immunol. 2016; 138: 1161-1169Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar demonstrated that TH17 cells assume an anti-inflammatory function and produce IL-10 in the absence of IL-1β, thereby suppressing TH cell proliferation and downregulating cytokines secreted by monocytes. However, exposure to IL-1β impairs IL-10 secretion by TH17 cells, which is seen in patients with Schnitzler syndrome, a disease characterized by spontaneous IL-1β secretion. IL-1β inhibition in patients with Schnitzler syndrome rescued IL-10 production by TH17 cells. Yee et al7Yee C.S. Massaad M.J. Bainter W. Ohsumi T.K. Föger N. Chan A.C. et al.Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.J Allergy Clin Immunol. 2016; 137: 879-888Abstract Full Text Full Text PDF PubMed Google Scholar identified the functions of the coiled-coil leucine zipper (CC) and C-terminal extension (CE) domains in the filamentous actin-binding protein coronin 1A through the study of patients expressing a truncated coronin 1A mutant lacking the CC and CE domains. The CC and CE domains were shown to be important for coronin 1A oligomerization and subcellular localization, regulation of filamentous actin content, in vivo T-cell survival, and host defense against viruses but were not essential for calcium flux or cell cytotoxicity. Two studies have further delineated the role of the guanine exchange factor (GEF) dedicator of cytokinesis 8 (DOCK8) in T-cell function. Janssen et al8Janssen E. Tohme M. Hedayat M. Leick M. Kumari S. Ramesh N. et al.A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton.J Clin Invest. 2016; 126: 3837-3851Crossref PubMed Scopus (0) Google Scholar showed that DOCK8 interacts directly with Wiskott-Aldrich syndrome (WAS)–interacting protein, which bridges DOCK8 to WAS protein and actin in T cells. The GEF activity of DOCK8 is essential for TCR-driven WAS protein activation, actin cytoskeleton reorganization, and subcortical actin cytoskeletal integrity, which in turn are important for filamentous actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T-cell transendothelial migration, and homing of T cells to the lymph nodes. Hyper-IgE syndrome (HIES) caused by autosomal dominant mutations in STAT3 or autosomal recessive mutations in DOCK8 have multiple overlapping features, including TH17 dysfunction. Keles et al9Keles S. Charbonnier L.M. Kabaleeswaran V. Reisli I. Genel F. Gulez N. et al.Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation.J Allergy Clin Immunol. 2016; 138: 1384-1394Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar demonstrated that patients with mutations in DOCK8 have a block in TH17 differentiation similar to that previously reported in patients with autosomal dominant STAT3 mutations. The authors showed that DOCK8 constitutively associates with STAT3 and regulates its phosphorylation through DOCK8 GEF activity. DOCK8 also promotes STAT3 translocation to the nucleus and consequently induces STAT3-dependent TH17 differentiation. Infection-triggered induction of hemophagocytic lymphohistiocytosis (HLH) in perforin-deficient mice, as well as in patients with familial HLH, leads to decreased regulatory T-cell numbers.10Humblet-Baron S. Schönefeldt S. Garcia-Perez J.E. Baron F. Pasciuto E. Liston A. IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis.J Allergy Clin Immunol. 2016; 138: 200-209Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This was attributed to changes in the homeostatic regulation of IL-2, specifically decreased IL-2 secretion, increased IL-2 consumption by activated CD8+ T cells, and increased secretion of soluble CD25 (IL-2 receptor α), which competes for IL-2. Reduction of levels of circulating IL-2, which is essential for the maintenance of regulatory T cells, thereby contributes to the persistence of inflammation in these patients. Several reports have expanded our understanding of T-cell function in patients with viral infections. IL-6 is known to induce IL-21 production by CD4+ T cells and is required for the development of TFH cells, which in turn promote production of antibodies by means of interaction with B cells through the production of IL-21. Yang et al11Yang R. Masters A.R. Fortner K.A. Champagne D.P. Yanguas-Casás N. Silberger D.J. et al.IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21–producing B helper CD8+ T cells.J Exp Med. 2016; 213: 2281-2291Crossref PubMed Google Scholar showed that IL-6 also induces CD8+ T cells to differentiate into cells that produce low levels of IFN-γ and high levels of IL-21, which facilitates isotype switching in B cells. This is particularly relevant for the secretion of virus-specific IgG during an influenza virus infection, thus identifying an additional contribution of CD8+ T cells in host immunity against viruses. Persistent TCR activation and signaling, as seen in patients with chronic viral infections, leads to T-cell exhaustion, a state characterized by compromised effector T-cell function. Termination of TCR signaling is achieved through multivesicular body–mediated lysosomal degradation of the TCR. Hu et al12Hu Y. Kim J.H. He K. Wan Q. Kim J. Flach M. et al.Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion.J Exp Med. 2016; 213: 2759-2772Crossref PubMed Scopus (0) Google Scholar showed that deficiency of transmembrane protein 16F (TMEM16F), the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes, amplifies T-cell activation. Chronic infection of TMEM16F-deficient mice with lymphocytic choriomeningitis virus resulted in increased T-cell activation in the early stages of infection and T-cell exhaustion at later stages. Mechanistically, the authors demonstrated that TMEM16F is located in late endosomes and is important for the formation of the multivesicular body, TCR degradation, and thus signal termination. Targeting of TMEM16F to enhance its function is a potential strategy for avoiding T-cell exhaustion in patients with chronic viral infections or cancer. Autoimmune lymphoproliferative syndrome is characterized by chronic lymphoproliferation and accumulation of TCRαβ+ CD4−CD8− DN T cells. Völkl et al13Völkl S. Rensing-Ehl A. Allgäuer A. Schreiner E. Lorenz M.R. Rohr J. et al.Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome.Blood. 2016; 128: 227-238Crossref PubMed Google Scholar showed that DN T cells and their CD4+ or CD8+ precursors have hyperactive mammalian target of rapamycin (mTOR) signaling, which can be ameliorated by rapamycin. Disturbances in humoral immunity manifest clinically as immune deficiency, autoimmunity, or allergy. Multiple studies have addressed the production and regulation of B cells and antibodies (Table II).14Cantaert T. Schickel J.N. Bannock J.M. Ng Y.S. Massad C. Delmotte F.R. et al.Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint.J Clin Invest. 2016; 126: 4289-4302Crossref PubMed Scopus (1) Google Scholar, 15Lindsley A.W. Saal H.M. Burrow T.A. Hopkin R.J. Shchelochkov O. Khandelwal P. et al.Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.J Allergy Clin Immunol. 2016; 137: 179-187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16Kane A. Lau A. Brink R. Tangye S.G. Deenick E.K. B-cell-specific STAT3 deficiency: Insight into the molecular basis of autosomal-dominant hyper-IgE syndrome.J Allergy Clin Immunol. 2016; 138: 1455-1458Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Kulkarni U. Karsten C.M. Kohler T. Hammerschmidt S. Bommert K. Tiburzy B. et al.IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration.J Allergy Clin Immunol. 2016; 137: 1487-1497Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Simon Q. Pers J.O. Cornec D. Le Pottier L. Mageed R.A. Hillion S. In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles.J Allergy Clin Immunol. 2016; 137: 1577-1584Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 19Morbach H. Schickel J.N. Cunningham-Rundles C. Conley M.E. Reisli I. Franco J.L. et al.CD19 controls Toll-like receptor 9 responses in human B cells.J Allergy Clin Immunol. 2016; 137: 889-898Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 20Szodoray P. Stanford S.M. Molberg Ø. Munthe L.A. Bottini N. Nakken B. T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity.J Allergy Clin Immunol. 2016; 138: 839-851Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21Meli A.P. Fontés G. Avery D.T. Leddon S.A. Tam M. Elliot M. et al.The integrin LFA-1 controls T follicular helper cell generation and maintenance.Immunity. 2016; 45: 831-846Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Cantaert et al14Cantaert T. Schickel J.N. Bannock J.M. Ng Y.S. Massad C. Delmotte F.R. et al.Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint.J Clin Invest. 2016; 126: 4289-4302Crossref PubMed Scopus (1) Google Scholar studied the mechanisms by which mutations in AICDA, which encodes activation-induced cytidine deaminase, impair peripheral B-cell tolerance. They found that B cells from patients with AICDA mutations produced increased autoreactive antibodies compared with those of control subjects and patients with uracil N-glycosylase (UNG) deficiency. UNG deficiency causes defective class-switch recombination, as seen in patients with activation-induced cytidine deaminase deficiency, but is distinguished by intact somatic hypermutation. Patients with AICDA mutations, but not UNG-deficient patients, had altered germinal center reactions, defective regulatory T-cell suppressive function, increased TFH cell production, and enhanced cytokine production. The authors postulated that somatic hypermutation regulates peripheral B-cell tolerance through production of highly mutated antibodies that eliminate antigens and prevent alterations in T-cell composition and function that favor autoimmunity.Table IISelected key advances in B-cell immunologyReferences•Decreased somatic hypermutation causes impaired peripheral B-cell tolerance in patients with AICDA mutations.14Cantaert T. Schickel J.N. Bannock J.M. Ng Y.S. Massad C. Delmotte F.R. et al.Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint.J Clin Invest. 2016; 126: 4289-4302Crossref PubMed Scopus (1) Google Scholar•Kabuki syndrome caused by KMT2D mutation leads to humoral immune deficiency with impaired terminal B-cell differentiation.15Lindsley A.W. Saal H.M. Burrow T.A. Hopkin R.J. Shchelochkov O. Khandelwal P. et al.Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.J Allergy Clin Immunol. 2016; 137: 179-187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar•B cell–intrinsic defective STAT3 signaling results in impaired specific antibody production and increased IgE levels.16Kane A. Lau A. Brink R. Tangye S.G. Deenick E.K. B-cell-specific STAT3 deficiency: Insight into the molecular basis of autosomal-dominant hyper-IgE syndrome.J Allergy Clin Immunol. 2016; 138: 1455-1458Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar•Overexpression of IL-10 in plasmacytosis inhibits neutrophil migration and results in increased susceptibility to bacterial infection.17Kulkarni U. Karsten C.M. Kohler T. Hammerschmidt S. Bommert K. Tiburzy B. et al.IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration.J Allergy Clin Immunol. 2016; 137: 1487-1497Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar•CD24highCD38high transitional B cells can be distinguished into subsets with distinct regulatory function profiles.18Simon Q. Pers J.O. Cornec D. Le Pottier L. Mageed R.A. Hillion S. In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles.J Allergy Clin Immunol. 2016; 137: 1577-1584Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar•CD19 mediates TLR9-induced B-cell activation, integrating TLR and BCR signaling.19Morbach H. Schickel J.N. Cunningham-Rundles C. Conley M.E. Reisli I. Franco J.L. et al.CD19 controls Toll-like receptor 9 responses in human B cells.J Allergy Clin Immunol. 2016; 137: 889-898Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar•Autoreactive naive IgD+IgM− B cells are rescued from anergy by TH2 signals through upregulation of CD45 activity.20Szodoray P. Stanford S.M. Molberg Ø. Munthe L.A. Bottini N. Nakken B. T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity.J Allergy Clin Immunol. 2016; 138: 839-851Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar•The integrin LFA-1 is required for TFH survival and differentiation in the germinal center.21Meli A.P. Fontés G. Avery D.T. Leddon S.A. Tam M. Elliot M. et al.The integrin LFA-1 controls T follicular helper cell generation and maintenance.Immunity. 2016; 45: 831-846Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Open table in a new tab Lindsley et al15Lindsley A.W. Saal H.M. Burrow T.A. Hopkin R.J. Shchelochkov O. Khandelwal P. et al.Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.J Allergy Clin Immunol. 2016; 137: 179-187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar studied the extent of humoral immunity impairment in patients with Kabuki syndrome caused by autosomal dominant mutations in lysine methyltransferase 2D (KMT2D). Affected patients have variable hypogammaglobulinemia, decreased numbers of total and class-switched memory B cells, and reduced rates of somatic hypermutation in IgG. Autoimmunity was found in a subset of patients with a specific missense mutation. The authors emphasized the importance of serial immune follow-up for patients with Kabuki syndrome. Using a mouse model of B cell lineage–specific inactivation of Stat3, Kane et al16Kane A. Lau A. Brink R. Tangye S.G. Deenick E.K. B-cell-specific STAT3 deficiency: Insight into the molecular basis of autosomal-dominant hyper-IgE syndrome.J Allergy Clin Immunol. 2016; 138: 1455-1458Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar observed impaired expansion of antigen-specific B cells, reduced serum antigen-specific IgM and IgG levels, significantly increased serum IgE levels, and impaired affinity maturation after immunization with a T cell–dependent antigen. The results highlight the role of defective B cell–intrinsic Stat3 signaling in causing the humoral immune defects observed in autosomal dominant HIES in human subjects. Kulkarni et al17Kulkarni U. Karsten C.M. Kohler T. Hammerschmidt S. Bommert K. Tiburzy B. et al.IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration.J Allergy Clin Immunol. 2016; 137: 1487-1497Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar examined the effect of IL-10 on neutrophil function in a murine myeloma model. IL-10 derived from normal and neoplastic cells inhibited neutrophil migration toward the anaphylatoxin C5a and suppressed neutrophil-dependent inflammation. Interestingly, the authors demonstrated increased susceptibility to streptococcal pneumonia in this mouse model that could be reversed with IL-10 receptor blockade. Simon et al18Simon Q. Pers J.O. Cornec D. Le Pottier L. Mageed R.A. Hillion S. In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles.J Allergy Clin Immunol. 2016; 137: 1577-1584Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar characterized CD24highCD38high transitional B cells in human subjects and reported 4 subsets of transitional B cells based on distinct phenotypic and regulatory function properties. In addition to transitional type 1 and type 2 B cells, the authors described anergic type 3 B cells and IL-10–producing CD27+ transitional B cells. These subsets were differentially represented in patients with specific autoimmune diseases, suggesting potential clinical utility for this classification. An essential role of CD19 in mediating Toll-like receptor (TLR) 9–induced human B-cell activation was reported by Morbach et al.19Morbach H. Schickel J.N. Cunningham-Rundles C. Conley M.E. Reisli I. Franco J.L. et al.CD19 controls Toll-like receptor 9 responses in human B cells.J Allergy Clin Immunol. 2016; 137: 889-898Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The authors found that CD19 deficiency not only interfered with B-cell receptor (BCR)–mediated B-cell activation but also led to impaired activation responses after TLR9 stimulation. The authors demonstrated that B-cell signaling downstream of TLR9 activation through the molecules phosphoinositide 3-kinase (PI3K), Bruton tyrosine kinase, and AKT was dependent on CD19. The subset of autoreactive B cells that undergo functional anergy and thus do not result in autoimmunity have been characterized as naive IgD+IgM− B cells. Szodoray et al20Szodoray P. Stanford S.M. Molberg Ø. Munthe L.A. Bottini N. Nakken B. T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity.J Allergy Clin Immunol. 2016; 138: 839-851Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar demonstrated that BCR signaling can be restored in naive IgD+IgM− B cells and they can be rescued from anergy on receiving TH2 signals (IL-4/CD40 ligand [CD40L]). TH2 signals increase the activity of the protein tyrosine phosphatase CD45, allowing activation of Lyn kinase and increasing BCR signaling. Meli et al21Meli A.P. Fontés G. Avery D.T. Leddon S.A. Tam M.
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