Sorting Out the Causes of ALPS
2005; Elsevier BV; Volume: 147; Issue: 5 Linguagem: Inglês
10.1016/j.jpeds.2005.09.025
ISSN1097-6833
Autores Tópico(s)Hepatitis B Virus Studies
ResumoAutoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of abnormal lymphocyte homeostasis. Defective programmed cell death of lymphocytes (apoptosis) through the Fas (CD95) pathway occupies a central role in the pathogenesis of ALPS. Homeostasis through apoptosis is important to remain within the limited containment capacity of the lymphoid compartment to eliminate autoreactive lymphocytes and to prevent malignant transformation of lymphocytes.1Lenardo M. Chan K.M. Hornung F. McFarland H. Siegel R. Wang J. Zheng L. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment.Annu Rev Immunol. 1999; 17: 221-253Crossref PubMed Scopus (842) Google Scholar Consequently, the main manifestations of ALPS are lymphoproliferation, reflected in lymphadenopathy and hepatosplenomegaly, autoimmune disease, directed mostly toward blood cells, and a highly increased risk of lymphoma.2Bleesing J.J. Autoimmune lymphoproliferative syndrome (ALPS).Curr Pharm Des. 2003; 9: 265-278Crossref PubMed Scopus (34) Google Scholar, 3Rieux-Laucat F. Fischer A. Deist F.L. Cell-death signaling and human disease.Curr Opin Immunol. 2003; 15: 325-331Crossref PubMed Scopus (108) Google Scholar, 4Straus S.E. Jaffe E.S. Puck J.M. Dale J.K. Elkon K.B. Rosen-Wolff A. et al.The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.Blood. 2001; 98: 194-200Crossref PubMed Scopus (355) Google Scholar The key laboratory abnormalities in ALPS are the accumulation of T-lymphocytes that express the alpha/beta (α/β) T-cell receptor, but lack expression of CD4 or CD8 (α/β-double negative T-cells [α/β-DNTCs]) in peripheral blood and lymphoid tissues, and defective Fas-mediated apoptosis in vitro.2Bleesing J.J. Autoimmune lymphoproliferative syndrome (ALPS).Curr Pharm Des. 2003; 9: 265-278Crossref PubMed Scopus (34) Google Scholar, 3Rieux-Laucat F. Fischer A. Deist F.L. Cell-death signaling and human disease.Curr Opin Immunol. 2003; 15: 325-331Crossref PubMed Scopus (108) Google Scholar The recognition that similar features are present in 2 murine models of ALPS led to the discovery of the molecular basis of the disorder.5Sneller M.C. Straus S.E. Jaffe E.S. Jaffe J.S. Fleisher T.A. Stetler-Stevenson M. et al.A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.J Clin Invest. 1992; 90: 334-341Crossref PubMed Scopus (255) Google Scholar, 6Fisher G.H. Rosenberg F.J. Straus S.E. Dale J.K. Middleton L.A. Lin A.Y. et al.Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.Cell. 1995; 81: 935-946Abstract Full Text PDF PubMed Scopus (1283) Google Scholar, 7Rieux-Laucat F. Le Deist F. Hivroz C. Roberts I.A. Debatin K.M. Fischer A. et al.Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.Science. 1995; 268: 1347-1349Crossref PubMed Scopus (1168) Google Scholar More than 200 patients with ALPS have now been identified with inherited (germ-line) heterozygous mutations in the gene encoding Fas (TNFRSF6, classified as ALPS type Ia). Many of these mutations are linked to defective Fas-mediated apoptosis through the mechanism of dominant negative interference.6Fisher G.H. Rosenberg F.J. Straus S.E. Dale J.K. Middleton L.A. Lin A.Y. et al.Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.Cell. 1995; 81: 935-946Abstract Full Text PDF PubMed Scopus (1283) Google Scholar, 8Jackson C.E. Fischer R.E. Hsu A.P. Anderson S.M. Choi Y. Wang J. et al.Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Am J Hum Genet. 1999; 64: 1002-1014Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Approximately 25% of patients diagnosed with ALPS do not have mutations in TNFRSF6. With the exception of several patients identified with mutations in the gene encoding Fas ligand (TNFSF6, ALPS type Ib) and the gene encoding caspase 10 (CASP10, ALPS type II), these patients currently lack a genetic diagnosis and are classified as ALPS type III.2Bleesing J.J. Autoimmune lymphoproliferative syndrome (ALPS).Curr Pharm Des. 2003; 9: 265-278Crossref PubMed Scopus (34) Google Scholar, 3Rieux-Laucat F. Fischer A. Deist F.L. Cell-death signaling and human disease.Curr Opin Immunol. 2003; 15: 325-331Crossref PubMed Scopus (108) Google Scholar In this issue of The Journal, Rössler et al9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar describe a patient with a typical presentation of ALPS, who was found to have a hitherto un-described somatic mutation in TNFRSF6 in her α/β-DNTCs, without having this mutation in her germ-line. Together with the patients recently described by Holzelova et al,10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar the tally now stands at 7 patients with ALPS with somatic mutations affecting Fas without germ-line mutations. These patients raise many questions, and pose some diagnostic dilemmas. Before discussing some of these, it is useful to review these patients as a group. All patients presented between 4 and 24 months of life with evidence of lymphadenopathy or splenomegaly: typical ages of initial presentation previously described for ALPS.2Bleesing J.J. Autoimmune lymphoproliferative syndrome (ALPS).Curr Pharm Des. 2003; 9: 265-278Crossref PubMed Scopus (34) Google Scholar, 9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar Autoimmunity was present in 5/7 patients and consisted of hemolytic anemia, thrombocytopenia, neutropenia and urticarial rash but was absent in the 2 youngest patients. An increased percentage of α/β-DNTCs (varying between 9% and 30%) was consistently found in all patients, whereas their Fas-mediated apoptosis assays were normal. No germ-line mutations were detected; heterozygous somatic mutations in TNFRSF6 were identified in sorted α/β-DNTCs in all patients. In 4 of 7, this involved mutations causing premature stop codons in exon 8; in one patient, exon 7 harbored a mutation, leading to a premature stop codon, whereas in the remaining 2, mutations affected exon 9 (one premature stop codon; one missense mutation).9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar Several of these mutations had previously been described at the germ-line level in patients with ALPS type Ia, associated with dominant-negative interference.10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar Somatic mutations, with its ensuing mosaicism, are not rare occurrences. Often considered in the context of cancer development, a variety of human diseases are associated with somatic mutations, eg, neurofibromatosis, McCune-Albright syndrome, and paroxysmal nocturnal hemoglobinuria.11Erickson R.P. Somatic mutation and human disease other than cancer.Mutat Res. 2003; 543: 125-136Crossref PubMed Scopus (88) Google Scholar The separation into 3 germ cell layers, namely mesoderm (eg, bone), endoderm (eg, liver), and ectoderm (eg, skin), has been used to time the occurrence of somatic mutations relative to embryonic development. Although this separation is far from absolute, it does suggest that somatic mutations occur during the earliest stages of embryogenesis, when they affect a sufficient number of progenitor cells to be able to cause disease. In certain disorders (eg, paroxysmal nocturnal hemoglobinuria) there is only a limited representation by mutated cells, and it has been proposed that some mechanism must be in place to ensure that the mutant cells have a survival advantage over wild-type cells.11Erickson R.P. Somatic mutation and human disease other than cancer.Mutat Res. 2003; 543: 125-136Crossref PubMed Scopus (88) Google Scholar, 12Johnson R.J. Hillmen P. Paroxysmal nocturnal haemoglobinuria: nature's gene therapy?.Mol Pathol. 2002; 55: 145-152Crossref PubMed Scopus (41) Google Scholar How do these observations relate to ALPS? If somatic mutagenesis involving TNFRSF6 similarly occurs at an early embryonic stage, one would expect to find multiple mutant cell types or lineages. This was not studied by Rössler et al9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar; however in 1 patient described by Holzelova et al,10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar mutations were found in a proportion of all hematopoietic cells, but not in cells of ectodermal origin. Additional cell types and tissues need to be analyzed before the timing of mutagenesis (embryonic, fetal, or postnatal) can be firmly established. Selective survival advantage of cells with abnormal Fas-mediated apoptosis during hematopoiesis and the immune response to (self) antigens appears to be the key factor determining their continued existence, accumulation in the α/β-DNTC compartment, and their role in causing ALPS. Many questions remain. For example, how do these terminally differentiated mutant cells cause autoimmunity? Are the somatically mutated lymphocytes at risk of becoming malignant? Could other components in the Fas pathway, such as Fas ligand or caspase 10 undergo somatic mutagenesis and cause ALPS? Lastly, could other autoimmune/lymphoproliferative disorders carry somatic mutations in genes that confer altered cell survival? The combination of chronic non-malignant lymphoproliferation and the presence of α/β-DNTCs, above a control population-based percentage/number, are widely accepted as required criteria for the diagnosis of ALPS.2Bleesing J.J. Autoimmune lymphoproliferative syndrome (ALPS).Curr Pharm Des. 2003; 9: 265-278Crossref PubMed Scopus (34) Google Scholar, 3Rieux-Laucat F. Fischer A. Deist F.L. Cell-death signaling and human disease.Curr Opin Immunol. 2003; 15: 325-331Crossref PubMed Scopus (108) Google Scholar The presence of autoimmunity occurs in most patients, but not necessarily at the time of initial presentation, and thus is not included in the required criteria. Although ALPS is a disorder of defective Fas-mediated apoptosis, the place of defective Fas-mediated apoptosis in vitro among the required criteria of ALPS is somewhat contentious. This is mainly due to the identification of patients with an ALPS phenotype, but with normal Fas-mediated apoptosis in vitro.13Ramenghi U. Bonissoni S. Migliaretti G. DeFranco S. Bottarel F. Gambaruto C. et al.Deficiency of the Fas apoptosis pathway without Fas gene mutations is a familial trait predisposing to development of autoimmune diseases and cancer.Blood. 2000; 95: 3176-3182Crossref PubMed Google Scholar, 14Hundt M. Posovszky C. Schmidt R.E. A new disorder of lymphocyte apoptosis: combination of autoimmunity, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death.Immunobiology. 2002; 206: 514-518Crossref PubMed Scopus (6) Google Scholar Rössler et al9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and Holzelova et al10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar suggest that inclusion of defective Fas-mediated apoptosis in vitro as a required criterion for ALPS prohibits patients with somatic mutations to be appropriately diagnosed. These 7 patients force us to consider that the laboratory tools to detect the apoptotic defect in vitro may fall short in identifying all our patients. What then should the diagnostic approach to ALPS look like to include this group of patients? An important starting point would be to keep an open mind, avoid required criteria, and focus on the most consistent and informative clinical and laboratory features. This could be done in the form of an algorithm that provides a stepwise approach with decision-making points, as suggested by Rössler et al.9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Alternatively, or in combination, one could assign points to these features as part of a scoring scheme, in which the probability of ALPS is determined by the total score. Evidence of chronic/recurrent lymphoproliferation, with or without the presence of autoimmune disease that targets 1 or more blood cell lineages, should remain the clinical entry point of the diagnostic process. Obtaining a detailed family history, for example using a scoring scheme, should be a priority, because somatic mutations are expected to be sporadic, whereas germ-line mutations are typically inherited in a heterozygous manner, such that relatives with ALPS or ALPS features can often be found, especially if the mutation affects the intracellular domains of Fas.8Jackson C.E. Fischer R.E. Hsu A.P. Anderson S.M. Choi Y. Wang J. et al.Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Am J Hum Genet. 1999; 64: 1002-1014Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 15Infante A.J. Britton H.A. DeNapoli T. Middelton L.A. Lenardo M.J. Jackson C.E. et al.The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis.J Pediatr. 1998; 133: 629-636Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Fortunately, all patients described by Rössler et al9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and Holzelova et al10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar showed an expansion of α/β-DNTCs. Thus the central laboratory component of any diagnostic approach should continue to focus on α/β-DNTCs. To improve sensitivity and specificity, and to help optimally allocate laboratory resources, additional (unique) immunophenotypic characteristics can be incorporated in the enumeration of α/β-DNTCs. This is especially relevant if the percentage of these cells in suspected patients is close to what can be found in age-matched healthy control subjects or if patients have been exposed to immunosuppressive drugs. Our laboratory uses the B220 marker as part of the ALPS evaluation panel.16Bleesing J.J. Brown M.R. Dale J.K. Straus S.E. Lenardo M.J. Puck J.M. et al.TcR-alpha/beta(+) CD4(−)CD8(−) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis.Clin Immunol. 2001; 100: 314-324Crossref PubMed Scopus (79) Google Scholar This marker is specific for α/β-DNTCs that arise on the basis of abnormal Fas-mediated apoptosis in vivo, setting these cells clearly apart from “normal” α/β-DNTCs, even in the context of immunosuppressive drugs, and can be used in cell sorting strategies.16Bleesing J.J. Brown M.R. Dale J.K. Straus S.E. Lenardo M.J. Puck J.M. et al.TcR-alpha/beta(+) CD4(−)CD8(−) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis.Clin Immunol. 2001; 100: 314-324Crossref PubMed Scopus (79) Google Scholar, 17Bleesing J.J. Morrow M.R. Uzel G. Fleisher T.A. Human T cell activation induces the expression of a novel CD45 isoform that is analogous to murine B220 and is associated with altered O-glycan synthesis and onset of apoptosis.Cell Immunol. 2001; 213: 72-81Crossref PubMed Scopus (20) Google Scholar, 18Renno T. Attinger A. Rimoldi D. Hahne M. Tschopp J. MacDonald H.R. Expression of B220 on activated T cell blasts precedes apoptosis.Eur J Immunol. 1998; 28: 540-547Crossref PubMed Scopus (63) Google Scholar Other immunologic findings, such as the presence of CD5-expressing B-cells, lack of CD25-expressing T-cells, elevated levels of immunoglobulin G and A, autoantibodies typically directed at blood cells, and elevated levels of interleukin-10, can be incorporated in a scoring system, in combination with other clinical features (eg, skin rashes, and absence or presence of constitutional symptoms) to provide supportive evidence.2Bleesing J.J. Autoimmune lymphoproliferative syndrome (ALPS).Curr Pharm Des. 2003; 9: 265-278Crossref PubMed Scopus (34) Google Scholar, 19Bleesing J.J. Brown M.R. Straus S.E. Dale J.K. Siegel R.M. Johnson M. et al.Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.Blood. 2001; 98: 2466-2473Crossref PubMed Scopus (121) Google Scholar, 20Lopatin U. Yao X. Williams R.K. Bleesing J.J. Dale J.K. Wong D. et al.Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression.Blood. 2001; 97: 3161-3170Crossref PubMed Scopus (86) Google Scholar The recognition that inherited mutations affecting the intracellular domains of Fas are associated with increased penetrance of ALPS can be exploited by measuring the most informative parameters, for example, α/β-DNTCs and interleukin-10 in the appropriate family members.8Jackson C.E. Fischer R.E. Hsu A.P. Anderson S.M. Choi Y. Wang J. et al.Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Am J Hum Genet. 1999; 64: 1002-1014Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 19Bleesing J.J. Brown M.R. Straus S.E. Dale J.K. Siegel R.M. Johnson M. et al.Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.Blood. 2001; 98: 2466-2473Crossref PubMed Scopus (121) Google Scholar, 20Lopatin U. Yao X. Williams R.K. Bleesing J.J. Dale J.K. Wong D. et al.Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression.Blood. 2001; 97: 3161-3170Crossref PubMed Scopus (86) Google Scholar At this stage in the diagnostic evaluation, one should be able to determine the likelihood of ALPS. Depending on the information (score) gathered thus far, as well as on availability of diagnostic procedures, including in vitro Fas-mediated apoptosis assays, genetic analysis of TNFRSF6, and access to cell sorting, the next phase of the algorithm can be navigated in several ways. In the case of a probable family history of ALPS, it may be appropriate to focus on genetic analysis of germ-line mutations in TNFRSF6. Conversely, in the case of sporadic ALPS, or the lack of access to genetic testing, it may be appropriate to proceed with measuring Fas-mediated apoptosis in vitro. If, after completing these approaches, the diagnosis remains unclear, a somatic TNFRSF6 mutation should be considered. Confirmation requires cell sorting (selection) of α/β-DNTCs and genetic analysis of sorted cells and control cells (eg, “non-selected” cells, fibroblasts). To ensure appropriate sensitivity (detecting somatic mutations in α/β-DNTCs) and specificity (lack of these mutations in control cells), direct sequencing may not be sufficient; cloning and sequencing of TNFRSF6-specific PCR products or mutation-specific quantitative polymerase chain reaction may be required.9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar Obviously, much of the navigation through the algorithm will take place at institutions equipped to handling these technically challenging procedures. The patients described by Rössler et al9Rössler J. Enders A. Lahr G. Heitger A. Winkler K. Fuchs H. et al.Identical phenotype in patients with somatic and germ line CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome.J Pediatr. 2005; : 691-694Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and Holzelova et al10Holzelova E. Vonarbourg C. Stolzenberg M.C. Arkwright P.D. Selz F. Prieur A.M. et al.Autoimmune lymphoproliferative syndrome with somatic Fas mutations.N Engl J Med. 2004; 351: 1409-1418Crossref PubMed Scopus (218) Google Scholar invite us to reconsider the diagnosis of ALPS in a proportion of our patients, and to reexamine the diagnostic approach to ALPS. It is likely that this group of seven will continue to expand, hopefully catalyzing an ongoing discussion regarding ALPS diagnosis, classification, and pathogenesis. Sorting out the different causes of ALPS will teach us valuable lessons regarding the nature of somatic mutagenesis, especially in the context of survival advantage and the importance of the Fas pathway of cellular suicide, as well as the functional contribution of different cell populations (eg, α/β-DNTCs, other T-cells, B-cells) and factors (eg, interleukin 10) to the complicated pathogenesis of ALPS. In turn these lessons may cross-fertilize many other areas of investigation that focus on somatic mutagenesis, autoimmunity, lymphoproliferation, homeostasis within the immune system, and malignant transformation of lymphocytes.
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