Somatic Mutations — Not Just for Cancer Anymore
http://www.100md.com
《新英格兰医药杂志》
Opportunities for genetic errors during reproduction are so frequent that one wonders how any of us turn out healthy. Although many of these errors are inconsequential, and some can beneficially increase human diversity, germ-line mutations underlie risks for thousands of diseases. Genetic diseases, however, need not be inherited through the germ line: somatic mutations can arise in discrete cell lineages early in embryonic development or during postnatal life. The implications of somatic mutations are best known in the field of oncology. As predicted by Robert Weinberg two decades ago, and elegantly elucidated with regard to colon cancer by Bert Vogelstein, many cancers arise from single cells through the accretion of somatic mutations that afford growth and survival advantages. This insight from the field of cancer is now being extended to nonmalignant diseases. In a recent Journal article, Schwartz discussed mutations arising in hematopoietic cells in paroxysmal nocturnal hematuria,1 and in this issue of the Journal, Holzelova and colleagues (pages 1409–1418) teach us that somatic mutations can also cause an autoimmune disease.
In 1967, Canale and Smith described children who had chronic, nonmalignant hypersplenism, lymphadenopathy, and autoimmunity. A clue to the pathogenesis of this condition, which is now called the autoimmune lymphoproliferative syndrome (ALPS), was the recognition that two patients with the syndrome had elevated numbers of lymphocytes bearing / T-cell receptors but lacking CD4 or CD8 surface determinants.2 These lymphocytes were thus called double-negative T cells. This finding in ALPS was reminiscent of the phenotype of MRL lpr/lpr mice, whose T cells also fail to express the cell-surface receptor Fas, a mediator of programmed cell death, or apoptosis. In 1995, two groups described eight patients with ALPS, including two siblings, in whom lymphoproliferation, autoimmunity, and abundant double-negative T cells were associated with germ-line mutations in the gene that encodes Fas.3,4 More than 200 families with hereditary ALPS have now been described (http://research.nhgri.nih.gov/alps/).
In contrast to the homozygous recessive murine lpr mutation that causes a loss of Fas expression, most humans with ALPS have heterozygous mutations that encode abnormal Fas proteins. These proteins exhibit dominant interference with normal Fas molecules in trimeric apoptosis-signaling complexes. Because Fas-mediated apoptosis is a prominent mechanism for eliminating lymphocytes that have been activated by antigen (see Figure), lymphocytes with Fas defects escape apoptosis and accumulate, causing lymphadenopathy and splenomegaly. It is believed that some of the excess, aging lymphocytes lose their CD4 or CD8 coreceptors and become double-negative T cells. Other lymphocytes may bind to host antigens and cause autoimmune hemolytic anemia, neutropenia, thrombocytopenia, and other autoimmune conditions. Criteria to establish a diagnosis of ALPS include chronic nonmalignant splenomegaly or lymphadenopathy, expansion of /+ double-negative T cells, and defective lymphocyte apoptosis (demonstrable in vitro). Overt autoimmunity occurs in most patients. Inherited Fas defects greatly increase the risk of lymphomas of diverse histologic types,5 as further illustrated by the report of Clementi et al. in this issue of the Journal (pages 1419–1424).
Figure. Survival Advantage and Effects of Lymphocytes with Somatic Fas Mutations.
Normal lymphocyte homeostasis depends on maintaining a balance between the expansion of naive cells and their elimination by apoptosis, with a small minority of the cells that are generated after stimulation persisting as memory lymphocytes. Somatic mutations in a fraction of naive cells (brown) lead to their persistence as double-negative T cells, premalignant cells, and autoreactive cells that can mediate autoimmune responses.
Studies of additional patients have revealed that the case criteria for ALPS were met in only about half of those who had lymphoproliferation and autoimmunity; among the patients who did meet the criteria, one fourth lacked Fas mutations in DNA from whole blood. We now know that ALPS is also rarely associated with mutations in the Fas ligand or in caspases 8 and 10, which transduce the death signal triggered by Fas. Our classification system (see Table) categorizes cases in which no mutation has been identified as ALPS type III. In our series of 178 cases studied at the National Institutes of Health, 42 were classified as ALPS type III.
Table. Categorization of ALPS Cases According to Underlying Gene Defects.
Holzelova et al. provide new insights into causation in some patients with this enigmatic type of ALPS. Pursuing the hypothesis that double-negative T cells in patients with ALPS accumulate because they resist apoptosis, these investigators searched for somatic mutations of Fas in isolated double-negative T cells from patients with type III ALPS. Not only were Fas mutations detected in this durable cell population, but they were of the intracellular, dominant-interfering type associated with the most highly penetrant cases of familial ALPS. The origin of mutations was traced back through the T-cell lineage and, in one case, as far as CD34+ hematopoietic progenitor cells, but the mutations were absent in epithelial cells from the mouth or skin and hence were somatic rather than germ-line mutations.
These observations raise many questions. How does ALPS develop in patients in whom somatic mutations are predominantly limited to a minor, nonproliferating population of double-negative T cells? If mutant B cells and single-positive T cells (i.e., CD4+ or CD8+ T cells) cause the disease, why aren't these cells readily detected in the blood? Are they lurking in the enlarged lymph nodes and spleen, where they presumably mediate the autoimmune destruction of blood elements? In fact, a lymph node from one of the patients studied by Holzelova et al. (Patient 4) showed the typical paracortical lymphoid hyperplasia of ALPS.
Are the autoantibodies in ALPS a primary result of long-lived autoreactive B cells with defective Fas? Not necessarily. As shown by Uri Lopatin and our colleagues, double-negative T cells in ALPS greatly overproduce interleukin-10, an important B-cell stimulator and driver of type 2 T-helper responses. Thus, superannuated double-negative T cells could promote the proliferation of nonmutated lymphocytes, thereby indirectly leading to autoimmune disease.
Are patients in whom ALPS is caused by somatic mutations at risk for blood-cell cancers? The findings of Holzelova et al. suggest that such patients, like those with inherited Fas defects, are at risk for cancers originating in Fas-defective hematopoietic cells. A substantial proportion of sporadic lymphomas and other cancers in previously healthy subjects bear somatic mutations in Fas.
Do somatic mutations in apoptosis pathways underlie more common autoimmune diseases, such as lupus and rheumatoid arthritis? After the discovery of ALPS, investigators looked in vain for germ-line mutations in apoptosis genes, but lymphocytes at the sites of injury should now be reexamined for somatic mutations. Indeed, the powerful combination of somatic mutation and natural selection for increased survival may explain the evolution of diverse human diseases whose origins are currently unknown.
Source Information
From the Genetics and Molecular Biology Branch, National Human Genome Research Institute (J.M.P), and the Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (S.E.S.), National Institutes of Health, Bethesda, Md.
References
Schwartz RS. Black mornings, yellow sunsets -- a day with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:537-538.
Sneller MC, Straus SE, Jaffe ES, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest 1992;90:334-341.
Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995;268:1347-1349.
Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935-946.
Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 2001;98:194-200.(Jennifer M. Puck, M.D., a)
In 1967, Canale and Smith described children who had chronic, nonmalignant hypersplenism, lymphadenopathy, and autoimmunity. A clue to the pathogenesis of this condition, which is now called the autoimmune lymphoproliferative syndrome (ALPS), was the recognition that two patients with the syndrome had elevated numbers of lymphocytes bearing / T-cell receptors but lacking CD4 or CD8 surface determinants.2 These lymphocytes were thus called double-negative T cells. This finding in ALPS was reminiscent of the phenotype of MRL lpr/lpr mice, whose T cells also fail to express the cell-surface receptor Fas, a mediator of programmed cell death, or apoptosis. In 1995, two groups described eight patients with ALPS, including two siblings, in whom lymphoproliferation, autoimmunity, and abundant double-negative T cells were associated with germ-line mutations in the gene that encodes Fas.3,4 More than 200 families with hereditary ALPS have now been described (http://research.nhgri.nih.gov/alps/).
In contrast to the homozygous recessive murine lpr mutation that causes a loss of Fas expression, most humans with ALPS have heterozygous mutations that encode abnormal Fas proteins. These proteins exhibit dominant interference with normal Fas molecules in trimeric apoptosis-signaling complexes. Because Fas-mediated apoptosis is a prominent mechanism for eliminating lymphocytes that have been activated by antigen (see Figure), lymphocytes with Fas defects escape apoptosis and accumulate, causing lymphadenopathy and splenomegaly. It is believed that some of the excess, aging lymphocytes lose their CD4 or CD8 coreceptors and become double-negative T cells. Other lymphocytes may bind to host antigens and cause autoimmune hemolytic anemia, neutropenia, thrombocytopenia, and other autoimmune conditions. Criteria to establish a diagnosis of ALPS include chronic nonmalignant splenomegaly or lymphadenopathy, expansion of /+ double-negative T cells, and defective lymphocyte apoptosis (demonstrable in vitro). Overt autoimmunity occurs in most patients. Inherited Fas defects greatly increase the risk of lymphomas of diverse histologic types,5 as further illustrated by the report of Clementi et al. in this issue of the Journal (pages 1419–1424).
Figure. Survival Advantage and Effects of Lymphocytes with Somatic Fas Mutations.
Normal lymphocyte homeostasis depends on maintaining a balance between the expansion of naive cells and their elimination by apoptosis, with a small minority of the cells that are generated after stimulation persisting as memory lymphocytes. Somatic mutations in a fraction of naive cells (brown) lead to their persistence as double-negative T cells, premalignant cells, and autoreactive cells that can mediate autoimmune responses.
Studies of additional patients have revealed that the case criteria for ALPS were met in only about half of those who had lymphoproliferation and autoimmunity; among the patients who did meet the criteria, one fourth lacked Fas mutations in DNA from whole blood. We now know that ALPS is also rarely associated with mutations in the Fas ligand or in caspases 8 and 10, which transduce the death signal triggered by Fas. Our classification system (see Table) categorizes cases in which no mutation has been identified as ALPS type III. In our series of 178 cases studied at the National Institutes of Health, 42 were classified as ALPS type III.
Table. Categorization of ALPS Cases According to Underlying Gene Defects.
Holzelova et al. provide new insights into causation in some patients with this enigmatic type of ALPS. Pursuing the hypothesis that double-negative T cells in patients with ALPS accumulate because they resist apoptosis, these investigators searched for somatic mutations of Fas in isolated double-negative T cells from patients with type III ALPS. Not only were Fas mutations detected in this durable cell population, but they were of the intracellular, dominant-interfering type associated with the most highly penetrant cases of familial ALPS. The origin of mutations was traced back through the T-cell lineage and, in one case, as far as CD34+ hematopoietic progenitor cells, but the mutations were absent in epithelial cells from the mouth or skin and hence were somatic rather than germ-line mutations.
These observations raise many questions. How does ALPS develop in patients in whom somatic mutations are predominantly limited to a minor, nonproliferating population of double-negative T cells? If mutant B cells and single-positive T cells (i.e., CD4+ or CD8+ T cells) cause the disease, why aren't these cells readily detected in the blood? Are they lurking in the enlarged lymph nodes and spleen, where they presumably mediate the autoimmune destruction of blood elements? In fact, a lymph node from one of the patients studied by Holzelova et al. (Patient 4) showed the typical paracortical lymphoid hyperplasia of ALPS.
Are the autoantibodies in ALPS a primary result of long-lived autoreactive B cells with defective Fas? Not necessarily. As shown by Uri Lopatin and our colleagues, double-negative T cells in ALPS greatly overproduce interleukin-10, an important B-cell stimulator and driver of type 2 T-helper responses. Thus, superannuated double-negative T cells could promote the proliferation of nonmutated lymphocytes, thereby indirectly leading to autoimmune disease.
Are patients in whom ALPS is caused by somatic mutations at risk for blood-cell cancers? The findings of Holzelova et al. suggest that such patients, like those with inherited Fas defects, are at risk for cancers originating in Fas-defective hematopoietic cells. A substantial proportion of sporadic lymphomas and other cancers in previously healthy subjects bear somatic mutations in Fas.
Do somatic mutations in apoptosis pathways underlie more common autoimmune diseases, such as lupus and rheumatoid arthritis? After the discovery of ALPS, investigators looked in vain for germ-line mutations in apoptosis genes, but lymphocytes at the sites of injury should now be reexamined for somatic mutations. Indeed, the powerful combination of somatic mutation and natural selection for increased survival may explain the evolution of diverse human diseases whose origins are currently unknown.
Source Information
From the Genetics and Molecular Biology Branch, National Human Genome Research Institute (J.M.P), and the Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (S.E.S.), National Institutes of Health, Bethesda, Md.
References
Schwartz RS. Black mornings, yellow sunsets -- a day with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:537-538.
Sneller MC, Straus SE, Jaffe ES, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest 1992;90:334-341.
Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995;268:1347-1349.
Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935-946.
Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 2001;98:194-200.(Jennifer M. Puck, M.D., a)