Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders
2017; Elsevier BV; Volume: 139; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2017.01.004
ISSN1097-6825
AutoresLuigi D. Notarangelo, Thomas A. Fleisher,
Tópico(s)T-cell and B-cell Immunology
ResumoPrimary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many cases also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain-of-function mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders, moving beyond the more commonly seen loss-of-function mutations. The rapidly expanding genetic defects that have been identified in patients with previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID-specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block overactive or enhance underresponsive cellular pathways. Selected primary immunodeficiencies were chosen, the genetic defects of which have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine. Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many cases also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain-of-function mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders, moving beyond the more commonly seen loss-of-function mutations. The rapidly expanding genetic defects that have been identified in patients with previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID-specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block overactive or enhance underresponsive cellular pathways. Selected primary immunodeficiencies were chosen, the genetic defects of which have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: March 2017. Credit may be obtained for these courses until February 28, 2018.Copyright Statement: Copyright © 2017-2018. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Luigi D. Notarangelo, MD, and Thomas A. Fleisher, MDDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: L. D. Notarangelo is an Associate Editor for Clinical Immunology and the Journal of Clinical Immunology, is Editor-in-Chief of Frontiers in Immunology, has received grants from the National Institutes of Health, and has received royalties from UpToDate. T. A. Fleisher is President of the American Academy of Allergy, Asthma & Immunology; has received payment for lectures from the Boston City Wide Allergy Meeting and the Louisiana Society of Allergy, Asthma, and Immunology; and has received royalties as the coeditor of Clinical Immunology: Principles and Practice.Activity Objectives:1.To recognize the increasing spectrum of syndromes with immune dysregulation and immunodeficiency.2.To understand how the molecular pathology underlying these syndromes can be targeted by novel personalized treatments.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Snehal Patel, DO, Pamela Panaporn Tongchinsub, MD, Roula Altisheh MD, and Tara F. Carr, MD, FAAAAI.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.The number of genetically defined primary immunodeficiency disorders (PIDs) has increased significantly over the past 10 to 15 years1Picard C. Al-Herz W. Bousfiha A. Casanova J.L. Chatila T. Conley M.E. et al.Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.J Clin Immunol. 2015; 35: 696-726Crossref PubMed Scopus (517) Google Scholar related to the availability of positional cloning and, more recently, massively parallel (next-generation) sequencing. Investigations of previously uncharacterized patients using the latter technology is dramatically increasing our understanding of the genetic basis of PIDs well beyond purely developmental abnormalities to include a range of defects affecting specific aspects of immune signaling and also moving from exclusively loss-of-function (LOF) mutations to include gain-of-function (GOF) mutations. Associated with this expanding understanding of immunologic disorders is the recognition that many of the more recently characterized PIDs include significant immune dysregulation often manifesting as autoimmunity in addition to increased susceptibility to infection. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: March 2017. Credit may be obtained for these courses until February 28, 2018. Copyright Statement: Copyright © 2017-2018. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Luigi D. Notarangelo, MD, and Thomas A. Fleisher, MD Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: L. D. Notarangelo is an Associate Editor for Clinical Immunology and the Journal of Clinical Immunology, is Editor-in-Chief of Frontiers in Immunology, has received grants from the National Institutes of Health, and has received royalties from UpToDate. T. A. Fleisher is President of the American Academy of Allergy, Asthma & Immunology; has received payment for lectures from the Boston City Wide Allergy Meeting and the Louisiana Society of Allergy, Asthma, and Immunology; and has received royalties as the coeditor of Clinical Immunology: Principles and Practice. Activity Objectives:1.To recognize the increasing spectrum of syndromes with immune dysregulation and immunodeficiency.2.To understand how the molecular pathology underlying these syndromes can be targeted by novel personalized treatments. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Snehal Patel, DO, Pamela Panaporn Tongchinsub, MD, Roula Altisheh MD, and Tara F. Carr, MD, FAAAAI. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. The capacity to precisely identify the molecular basis of an immunologic disorder has also opened the door to targeted therapies focused on either enhancing or inhibiting the consequences of an individual defect. This approach represents one of the central components of precision medicine (ie, therapy directed at the specific causative defect of a particular disorder rather than applying a nonspecific therapeutic approach). It is highly likely that the identification of new genetic defects associated with immune dysfunction will lead to additional examples of targeted therapeutic approaches for optimal clinical management of the patients affected by immune disorders. In this article we present the clinical phenotype of a number of more recently characterized PIDs and introduce specific therapeutic approaches that have emerged based on the current understanding of the molecular defect linked to each disorder. Because of space limitations, this focused discussion does not address the obvious importance of identifying the PID genotype when considering possible gene therapy or the potential contribution of the severe combined immunodeficiency genotype in the optimal approach for immune reconstitution associated with hematopoietic stem cell transplantation (HSCT). PIK3CD GOF mutations result in an immunologic disorder that causes accumulation of senescent T cells, lymphadenopathy, immunodeficiency, and autoimmunity. This disease is referred to either as activated phosphoinositide 3-kinase syndrome (APDS) or p110δ-activating mutation causing accumulation of senescent T cells, lymphadenopathy, and immunodeficiency (PASLI).2Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (430) Google Scholar, 3Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (456) Google Scholar, 4Elgizouli M. Lowe D.M. Speckmann C. Schubert D. Hulsdunker J. Eskandarian Z. et al.Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency.Clin Exp Immunol. 2016; 183: 221-229Crossref PubMed Scopus (74) Google Scholar To date, there have been 4 different heterozygous mutations defined producing GOF mutations that are associated with the following amino acid changes: E1021K, N334K, E525K, and C416R, with E1021K being by far the most common. Constitutive activation of phosphoinositide 3-kinase (PI3K) δ can also result from heterozygous splice site mutations of the PIK3R1 gene, encoding for the p85α subunit of the molecule.5Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (174) Google Scholar, 6Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (186) Google Scholar By removing the p110δ-binding site, these splice site mutations release p110δ from the inhibitory control mediated by the p85α subunit. This condition is also referred to as APDS2. The clinical presentation of APDS/PASLI and APDS2 typically begins with recurrent sinopulmonary infections in virtually all patients.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar, 8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar The onset of infections is typically in childhood, ranging from infancy until the early school years. The pulmonary infections are associated with a variety of bacterial pathogens but most commonly involve Streptococcus pneumoniae and Haemophilus influenzae. In studies to date, bronchiectasis has been found to be caused commonly by the frequency and chronicity of pulmonary infections.4Elgizouli M. Lowe D.M. Speckmann C. Schubert D. Hulsdunker J. Eskandarian Z. et al.Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency.Clin Exp Immunol. 2016; 183: 221-229Crossref PubMed Scopus (74) Google Scholar, 7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar, 8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Recurrent or persistent Herpesviridae family virus infections are also seen in about half of these patients, including EBV, cytomegalovirus, herpes simplex virus, and varicella zoster virus.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar Noninfectious complications include nonneoplastic lymphadenopathy, splenomegaly, and/or hepatomegaly in the majority of patients, as well as autoimmune disease (approximately 40%), nodular mucosal lymphoid hyperplasia (approximately 30%), and enteropathy (approximately 25%).7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar, 8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar The most serious complication of this disorder is the markedly increased frequency of lymphoma (particularly B-cell lymphoma), a development that represents one of the major causes of mortality.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar, 8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar As noted, one unique feature of this disease that is seen in about one third of patients is the presence of nodular mucosal lymphoid aggregates involving the pulmonary and/or gastrointestinal mucosa that have the appearance of cobblestones.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar Neurodevelopmental delay has been reported in approximately 20% to 30% of the patients and might represent a direct effect of dysregulation of PI3K activity in the central nervous system.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar, 8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Growth retardation has been noticed in 45% of patients with APDS2 but not in patients with PIK3CD mutations and might reflect dysregulated activity of p110α and p110β subunits.8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Immunologic findings include varied degrees of lymphopenia with decreased CD4 T-cell counts, reduced naive T-cell counts, increased senescent T-cell counts (CD3+CD8+CD57+) that do not proliferate normally, and increased effector memory CD8 T-cell counts in most patients.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar Furthermore, T-cell blasts from the patients show increased activation-induced cell death.5Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (174) Google Scholar The B-cell compartment demonstrates increased circulating transitional B-cell counts, decreased switched memory B-cell counts in many, increased IgM levels (approximately 80%) with varied deficiency of IgG and IgA, and, importantly, impaired antibody responses.7Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.06.021)Google Scholar, 8Elkaim E. Neven B. Bruneau J. Mitsui-Sekinaka K. Stanislas A. Heurtier L. et al.Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.J Allergy Clin Immunol. 2016; 138: 210-218.e9Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Based on the genetic findings, functional testing demonstrated increased AKT phosphorylation (Fig 1), as well as increased S6 phosphorylation as a result of augmented mammalian target of rapamycin (mTOR) signaling.2Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (430) Google Scholar, 3Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (456) Google Scholar, 5Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (174) Google Scholar, 6Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (186) Google Scholar Therefore mutations in the PI3K catalytic subunit p110δ clearly produce GOF. However, T-cell antigen receptor–induced calcium flux and nuclear factor κ nuclear translocation were found to be normal.3Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (456) Google Scholar This suggested that targeting mTOR signaling potentially could control the endogenous cellular activation resulting from the GOF mutation in the PI3K catalytic subunit p110δ. The potential to diminish the increased level of activation was studied in vitro with experiments using rapamycin as an inhibitor of mTOR, and these produced diminished S6 phosphorylation.3Lucas C.L. Kuehn H.S. Zhao F. Niemela J.E. Deenick E.K. Palendira U. et al.Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency.Nat Immunol. 2014; 15: 88-97Crossref PubMed Scopus (456) Google Scholar, 6Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (186) Google Scholar Furthermore, in vitro addition of a small-molecule inhibitor of p110δ (Leniolisib/CDZ173) to patients' T cells reduced intracellular levels of phosphatidylinositol-tris-phosphate2Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (430) Google Scholar and diminished AKT and S6 phosphorylation.5Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (174) Google Scholar, 6Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Scopus (186) Google Scholar Altogether, these data suggest that rapamycin and small-molecule inhibitors of p110δ could prove effective in managing these patients. The clinical outcome in patients with APDS/PASLI or APDS2 is often severe because of increased risk of infections and lymphoma. Accordingly, directed therapy could prove to be very valuable. Hematopoietic stem cell transplantation (HSCT) has been attempted in a small number of patients. According to a recent report, 9 of 11 patients who have received HSCT were alive at 8 months or more after transplantation.9Nademi Z. Slatter M.A. Dvorak C.C. Neven B. Fischer A. Suarez F. et al.Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome.J Allergy Clin Immunol. 2016; ([Epub ahead of print]. http://dx.doi.org/10.1016/j.jaci.2016.09.040)Google Scholar However, based on in vitro data, a recent trial has been initiated using the small-molecule inhibitor of the PI3K catalytic subunit p110δ (Leniolisib/CDZ173). The results in the first 6 patients were presented recently and showed a marked decrease in lymphadenopathy, reduction in senescent CD4 and CD8 T-cell counts, decrease in transitional B-cell counts, and normalization of naive B cells. This was accompanied by a dose-dependent reduction in AKT and S6 phosphorylation.10Rao VK, Christ AD, Su H, Kashyap A, Webster S, Sediva A, et al. Successful clinical study of Leniolisib (CDZ173), a small molecule PI3K-delta inhibitor in patients with APDS/PASLI. Presented at: ESID 17th Biennial Meeting; Barcelona, Spain; 2016.Google Scholar These encouraging results are being followed up with a larger phase II trial but suggest that a targeted therapy focused on the specific GOF mutation affecting the PI3K catalytic subunit p110δ could prove to be a relatively nontoxic directed therapy in patients with this condition. However, until additional patients are enrolled and long-term outcome is determined, this remains to be proved. Cytotoxic lymphocyte antigen 4 (CTLA4), also referred to as CD152, is an immune checkpoint receptor that turns down the immune response. CTLA4 has a high affinity for the ligands CD80 and CD86, which are expressed on antigen-presenting cells.11Krummel M.F. Allison J.P. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells.J Exp Med. 1996; 183: 2533-2540Crossref PubMed Scopus (776) Google Scholar This surface protein is constitutively expressed on regulatory T (Treg) cells and is expressed on other T cells after activation. Binding to CD80/CD86 by T cells expressing CTLA4 yields an inhibitory signal that prevents cell-cycle progression and T-cell activation. This contrasts with CD80/CD86 binding to CD28, which provides the costimulatory signal necessary for T cell–receptor based T-cell activation. Understanding the importance of the CTLA4 checkpoint in modulating immune responses leads to generation of a fusion molecule consisting of the extracellular domain of CTLA4 fused to the Fc region of IgG1 (abatacept) that functions in vivo as an inhibitor of T-cell activation, and this biologic is now US Food and Drug Administration approved for the treatment of refractory rheumatoid arthritis.12Herrero-Beaumont G. Martinez Calatrava M.J. Castaneda S. Abatacept mechanism of action: concordance with its clinical profile.Reumatol Clin. 2012; 8: 78-83Crossref PubMed Scopus (64) Google Scholar The primary side effects associated with abatacept include increased susceptibility to infections and increased risk for malignancy. In 2014, 2 publications reported on CTLA4 mutations in patients with recurrent sinopulmonary and viral infections, as well as significant autoimmunity.13Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. et al.Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (609) Google Scholar, 14Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (592) Google Scholar In both reports affected patients had clinical and laboratory features consistent with common variable immunodeficiency, including infectious complications and hypogammaglobulinemia, with the additional findings of significant infiltrative autoimmunity primarily affecting the lung, gastrointestinal tract, and nervous system, as well as autoimmune cytopenias. Whole-exome sequencing revealed heterozygous mutations in CTLA4 producing LOF associated with the mutant allele. Functional testing demonstrated that effector T cells were hyperactivated and forkhead box P3 (FOXP3)+ Treg cells had diminished CTLA4 expression (Fig 2), as well as decreased suppressor function. Treg cells also demonstrated a diminished capacity to transendocytose CD80 ex vivo as a reflection of another component contributing to the diminished regulatory capacity of Treg cells.14Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (592) Google Scholar In addition, patients demonstrated diminished CTLA4 expression after activation of conventional T cells, suggesting impairment of this checkpoint that controls immune responses, including those involving self-reactive T cells that escaped central deletion. Patients with CTLA4 haploinsufficiency also have a progressive loss of B cells associated with an increase in the autoreactive CD21lo B-cell subset.13Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. et al.Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (609) Google Scholar Importantly, certain family members with the same CTLA4 mutation had limited or no clinical findings, suggesting variable penetrance and/or expressivity of disease associated with the heterozygous CTLA4 muta
Referência(s)