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Flow Cytometry in the Diagnosis and Follow up of Human Primary Immunodeficiencies

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Flow Cytometry in the Diagnosis and Follow up of Human Primary Immunodeficiencies In this issue: Clinical flow cytometry in 2019 This is a Platinum Open Access Journal distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Flow cytometry in the diagnosis and follow up of human primary immunodeficiencies Ulrich Salzer1,2, Ulrich Sack3, Ilka Fuchs2,4 1 Department of Rheumatology & Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany 2 Centre of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany 3 Medical Faculty, Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany 4 Institute for Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine University of Freiburg, Germany ARTICLE INFO ABSTRACT Corresponding author: Primary immunodeficiencies (PID) comprise a group Ulrich Salzer, MD Center for Chronic Immunodeficiency (CCI) and of more than 300 mostly monogenetic disorders of Department of Rheumatology the immune system leading to infection susceptibil- and Clinical Immunology ity and a variety of associated clinical and immuno- Medical Center - University of Freiburg logical complications. In a majority of these disorders Hugstetterstr. 55 79106 Freiburg im Breisgau the absence, disproportions or dysfunction of leu- Germany cocyte subpopulations or of proteins expressed by Phone/Fax: +49 761 27035390 these cells are observed. These distinctive features E-mail: [email protected] are studied by multicolour flow cytometry and the Key words: results are used for diagnosis, follow up, classifica- flow cytometry, primary immunodeficiency, tion and therapy monitoring in patients with PIDs. diagnostics Although a definite diagnosis almost always relies on genetic analysis in PIDs, the results of flow cytometric diagnostics are pivotal in the initial diagnostic assess- ment of suspected PID patients and often guide the treating physician to a more selective and efficient genetic diagnostic procedure, even in the era of next generation sequencing technology. Furthermore, phenotypic and functional flow cytometry tests allow Page 407 eJIFCC2019Vol30No4pp407-422 Ulrich Salzer, Ulrich Sack, Ilka Fuchs Flow cytometry in the diagnosis and follow up of human primary immunodeficiencies to validate novel genetic variants and the map- monogenetic PID traits and untreated or pro- ping of complex disturbances of the immune gressive PID disease causes sequelae, secondary system in individual patients in a personalized changes and end organ damage. manner. In this review we give an overview Finally, secondary immunodeficiency caused on phenotypic, functional as well as disease/ by non-immunological disorders, environmen- protein specific flow cytometric assays in the tal factors and immunosuppressive or ablative diagnosis of PID and highlight diagnostic strat- therapeutic interventions have to be consid- egies and specialties for several selected PIDs ered especially in adult patients with manifest- by way of example. ing symptoms suspicious for PID. Since most of severe PIDs manifest with first symptoms soon after birth, new born screening programs have recently been successfully established in sev- INTRODUCTION eral countries to detect these forms of PIDs at The last report of the International Union of the earliest time point as possible (see article by Immunological Societies (IUIS) lists 354 inborn Wolf J et al in this issue). errors of immunity resulting in various forms of In summary, the complex clinical and immuno- primary immunodeficiencies (PID), which are logical presentations of the various PIDs require subdivided into nine categories: sensitive and specific diagnostic tests. Flow- cy 1. Severe and combined tometry emerged as a method of choice for the immunodeficiencies (SCID) study of PIDs, since it allows the fast and reli- 2. Combined immunodeficiencies able analysis of almost all branches of the im- with syndromic features mune system on a single cell level. 3. Predominantly antibody deficiencies The basic clinical and laboratory evaluation of 4. Immunodysregulatory disorders a patient with suspected PID should include a 5. Defects affecting phagocytes careful clinical history, paying special attention 6. Defects of innate immunity to the family history and the symptoms and 7. Autoinflammatory disorders features mentioned above, a complete dif- 8. Complement deficiencies ferential blood count, serum immunoglobulin 9. Phenocopies of PIDs (1,2) levels, a global complement function test and Although PIDs are generally considered as very specific antibody titers for vaccine antigens rare disorders individually, they form a clinical- (e.g. tetanus toxoid). ly relevant cohort as a group. The major clini- The individual flow cytometric diagnostic test- cal symptom in the majority of PIDs is infection ing will depend on the clinical presentation of susceptibility, which ranges from specific im- the patient and the results of basic laboratory munodeficiency to a single pathogen to broad tests. If a defect of adaptive immunity is sus- immune failure. However some PIDs are syn- pected then usually a basic lymphocyte phe- dromic disorders and many PIDs show addi- notyping will be performed followed by some tional clinical manifestations caused by immune more specific testing (e.g. extended phenotype dysregulation, including autoimmunity, lympho- of B-cells in patients with antibody deficiency). proliferation, granulomatous inflammation and The range of applications ranges from pheno- malignancy disposition. In addition, there is con- typic assays investigating the numbers and pro- siderable phenotypic variability in many of the portions of immune cells, functional analysis of Page 408 eJIFCC2019Vol30No4pp407-422 Ulrich Salzer, Ulrich Sack, Ilka Fuchs Flow cytometry in the diagnosis and follow up of human primary immunodeficiencies Table 1 Examples of basic and extended phenotypic assays, disease specific surface and intracellular protein analysis and functional assays to study PIDs* Basic phenotypic analysis Test Cell populations Indications Lymphocyte Basic screening for CD4+ T-cells, CD8+ T-cells, B cells, NK cells subpopulations PID, SCID CD4+CD45RA+ naïve T-cells, HLA DR+ activated T-cell SCID, CVID, CID, T-cells, CD8 effector cells, γ/δ T-cells, α/β double subpopulations ALPS negative T-cells, regulatory T-cells IgD+CD27- naïve B-cells, IgD+CD27+ non-switched primary antibody B-cell memory, IgD-CD27+ switched memory, transitional deficiency, CVID, subpopulations B-cells, plasmablasts, CD21low B-cells CID Extended phenotypic analysis Test Cell populations Indications dendritic cell CD123+ plasmacytoid dendritic cells, GATA2 subpopulations CD11c+ myeloid dendritic cells deficiency regulatory T-cells CD4+CD25+ FoxP3+ regulatory T-cells IPEX syndrome recent thymic CD4+CD45RA+CD31+ T-cells SCID, DGS emigrants TCR repertoire T-cell Vβ chain variant expression SCID, CID analysis on CD4 and CD8 T-cells Functional assays to study PIDs Test Cell populations Indications oxidative burst chronic granulomatous disease, granulocytes assay inflammatory bowel disease CD4+ and CD8+ T-cells after stimulation with T-cell proliferation SCID, CVID, CID PHA, anti-CD3, anti-CD3 and anti-CD28 Page 409 eJIFCC2019Vol30No4pp407-422 Ulrich Salzer, Ulrich Sack, Ilka Fuchs Flow cytometry in the diagnosis and follow up of human primary immunodeficiencies CD107a expression NK cell familial hemophagocytic on stimulated or resting degranulation lymphohistiocytosis NK cells IL-17/IFNγ PMA/Ionomycin chronic mucocutaneous candidiasis, production stimulated T-cells Hyper IgE syndrome Disease specific surface and intracellular protein analysis Test Cell populations Indications BTK monocytes X-linked agammaglobulinemia WASp lymphocyte subsets Wiskott Aldrich syndrome CD40L activated T-cells X-linked Hyper IgM syndrome SAP lymphocyte subsets X-linked lymphoproliferative disorder type 1 XIAP lymphocyte subsets X-linked lymphoproliferative disorder type 2 Perforin NK cells FHL type 2 * ALPS: autoimmune lymphoproliferative syndrome; BTK: bruton tyrosine kinase; CID: combined immunodeficiency; CVID: common variable immunodeficiency; DGS: DiGeorge Syndrome; FHL: familial hemophagocytic lymphohistiocyto- sis; IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X linked; SAP: SLAM-associated protein; SCID: severe combined immunodeficiency; TCR: T-cell receptor; WASp: Wiskott Aldrich syndrome protein. cellular processes (e.g. proliferation, cytokine parameter and setup individually. Especially for secretion, cytotoxicity) to the direct analysis functional tests, in house reference values need of potentially mutated proteins in disease spe- to be determined and checked by appropriate cific assays (Table 1). Usually these techniques tests on a regular basis. Since defined biological are combined to allow the study of dynamic control materials for most of the assays will not processes in specific cell subpopulations (e.g. be commercially available, the parallel testing degranulation of NK lymphocytes) or protein of healthy controls for each diagnostic proce- expression in specific cell populations after dure is highly recommended. If available, stan- stimulation like e.g. CD40L expression in acti- dardized reagents and procedures should be vated T-cells (see Table 1). used and followed. The setup and performance
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