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      Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

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          Abstract

          Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis.

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          Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis.

          R. Watanabe-Fukunaga, C Brannan, N. G. Copeland … (1992)
          Fas antigen is a cell-surface protein that mediates apoptosis. It is expressed in various tissues including the thymus and has structural homology with a number of cell-surface receptors, including tumour necrosis factor receptor and nerve growth factor receptor. Mice carrying the lymphoproliferation (lpr) mutation have defects in the Fas antigen gene. The lpr mice develop lymphadenopathy and suffer from a systemic lupus erythematosus-like autoimmune disease, indicating an important role for Fas antigen in the negative selection of autoreactive T cells in the thymus.
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            Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.

            Galen Fisher, Fredric J Rosenberg, Stephen E Straus … (1995)
            Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.
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              AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.

              Bernice Lo, Kejian Zhang, Wei Lu … (2015)
              Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.
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                Author and article information

                Journal
                Journal ID (nlm-ta): F1000Res
                Journal ID (iso-abbrev): F1000Res
                Journal ID (pmc): F1000Research
                Title: F1000Research
                Publisher: F1000 Research Limited (London, UK )
                ISSN (Electronic): 2046-1402
                Publication date (Electronic): 1 November 2017
                Publication date Collection: 2017
                Volume: 6
                Electronic Location Identifier: 1928
                Affiliations
                [1 ]Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
                Author notes

                Competing interests: The authors declare that they have no competing interests.

                Author information
                https://orcid.org/0000-0001-7373-8987
                Article
                DOI: 10.12688/f1000research.11545.1
                PMC ID: 5668920
                PubMed ID: 29123652
                SO-VID: 77b75a51-1783-418e-9db5-b49d36242200
                Copyright © Copyright: © 2017 Bride K and Teachey D
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 2 November 2017
                Funding
                This manuscript was supported by funding from Cures within Reach and the Barbara Brodsky Foundation.
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Review
                Subject: Articles
                Subject: Anemias & Hypocellular Marrow Disorders
                Subject: Autoimmunity
                Subject: Hematological Disorders
                Subject: Hematopoietic Stem Cells
                Subject: Leukemia & Proliferative Disorders of Hematic Cells

                Keywords: autoimmune,cytopenias,sirolimus,mmf,double negative t cells,lymphoproliferative disease,fas/fasl,targeted therapy
                Data availability:
                Keywords: autoimmune, cytopenias, sirolimus, mmf, double negative t cells, lymphoproliferative disease, fas/fasl, targeted therapy

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