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An Inherited Disorder of Lymphocyte Apoptosis: The Autoimmune Lymphoproliferative Syndrome FREE

Moderator: Stephen E. Straus, MD; Discussants: Michael Sneller, MD; Michael J. Lenardo, MD; Jennifer M. Puck, MD; and Warren Strober, MD
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For definitions of terms used in the text, see Glossary.


Ann Intern Med. 1999;130(7):591-601. doi:10.7326/0003-4819-130-7-199904060-00020
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The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon “double-negative” CD3+ CD4 CD8 T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma.

Dr. Stephen Straus (Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases [NIAID], National Institutes of Health [NIH], Bethesda, Maryland): The autoimmune lymphoproliferative syndrome (ALPS) is a recently defined illness that arises in early childhood and can have fatal complications (18). It is associated with prominent nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune manifestations. Underlying ALPS are heritable mutations in genes that regulate lymphocyte survival by triggering programmed death of lymphocytes, or apoptosis. More important than the mere description of ALPS, however, are the novel insights that this description affords into the mechanisms that regulate lymphocyte homeostasis and contribute to autoimmunity.

Selected features of ALPS have been recognized for decades, but the full-blown syndrome is rare and has only recently been appreciated. Several authors have described families with significant adenopathy and splenomegaly (913) and other families with hemolytic anemia, thrombocytopenia, or neutropenia in association with circulating autoantibodies (1420).

Splenomegaly is a feature of autoimmune diseases (such as the Felty syndrome), and moderate lymphadenopathy is seen in up to 70% of patients with lupus (21). The constellation of lymphadenopathy, splenomegaly, and autoimmune cytopenia, however, was described by Canale and Smith in 1967 (22). Weisdorf and Krivit (23) and others (2425) noted that similar patients had decreased proportions or function of lymphocyte subsets. Contemporary evaluation of some of these older cases, including a family followed at the NIH, has shown them to be cases of ALPS (4, 13; Straus SE. Unpublished data).

Clues to the nature of some of these familial diseases emerged in the early 1990s, when we realized that affected patients resembled mice with the MRL/lpr phenotype; these mice exhibit progressive lymphoproliferation and autoantibody-mediated renal and vascular disease (1, 2627). Moreover, the usually rare subset of T cells that show neither the CD4 nor the CD8 co-receptors (CD3+ CD4 CD8 ), or “double-negative” cells, circulates in increased numbers both in these mice and in our patients.

In 1989, Trauth and coworkers (28) reported that a protein called Apo-1 triggered apoptosis of lymphocytes. In 1992, Watanabe-Fukunaga and colleagues (29) found that lpr mice failed to express that same antigen, which they called Fas and, later, CD95. In 1994, the APT1 gene encoding the human homologue of murine Fas was cloned (30). Shortly thereafter, Rieux-Laucat and associates in France (2) and Fisher and colleagues at the NIH (3) demonstrated defective apoptosis and specific Fas mutations in eight children with ALPS. In the ensuing years, more than 40 similar patients have been described (48).

The autoimmune lymphoproliferative syndrome (sometimes called the Canale-Smith syndrome [4]] represents a failure of apoptotic mechanisms that help maintain normal lymphocyte homeostasis, with a consequent accumulation of lymphoid mass and persistence of autoreactive cells. It is operationally defined as chronic, nonmalignant lymphoproliferation in patients with 1) an elevated percentage [>1%] of double-negative T cells and 2) defective lymphocyte apoptosis that produces a characteristic, if not pathognomic, pathologic picture on microscopic section of the lymph node or spleen (31). Autoimmunity is evident at some point in almost all affected patients. Most cases of ALPS are associated with specific Fas mutations, and yet-undefined mutations in other apoptosis genes are thought to underlie cases in patients with normal Fas. One remarkable case from our clinic shows many features of ALPS (Figure 1).

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Figure 1.
Clinical, radiologic, and histologic features of patients with the autoimmune lymphoproliferative syndrome. A.[6]B.C.D.E.++F.G.

Frontal view of National Institutes of Health patient 2. (Reproduced with permission from Sneller and colleagues .) Lymph node from patient 2 showing follicular hyperplasia and plasmacytosis (hematoxylin and eosin). (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD3. (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD4. (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD8. Few of the cells that stain reddish brown for CD3 are CD4 or CD8 . (Courtesy of Dr. Elaine Jaffe.) Computed tomographic scan through the upper thorax and axillae and abdomen of patient 23 showing marked paratracheal, anterior mediastinal, and axillary adenopathy. (Courtesy of Dr. Nilo Avila.) Computed tomographic scan through the upper thorax and axillae and abdomen of patient 23 showing hepatosplenomegaly. (Courtesy of Dr. Nilo Avila.) For panels B to E, original magnifications were ×200. For panels C to E, the stain used was immunoperoxidase.

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At age 18 months, NIH ALPS patient 2 was noted to have adenopathy, splenomegaly, and anemia (1, 3, 6). She underwent splenectomy at age 2 years for refractory anemia. Biopsies of splenic tissue, liver, lymph node, and bone marrow were nondiagnostic. Clinical photographs (Figure 1 A) and computed tomographic scans (Figures 1F and 1G) confirmed the presence of persistent, massive enlargement of all lymph node chains and organomegaly. Laboratory studies showed continuing anemia, polyclonal gammopathy, and positive results on a direct Coombs test. Autoimmune manifestations have included glomerulonephritis at age 2 years, idiopathic thrombocytopenic purpura (ITP) at age 9 years, and autoimmune biliary disease since age 10 years. Lymphocyte phenotyping showed absolute increases in B-cell and T-cell counts with a polyclonal expansion of T cells, 25% of which were double negative. The lymph nodes showed lymphoid hyperplasia and plasmacytosis (Figure 1 B), and more than 50% of T cells were double negative (Figures 1C, 1D, and 1E). In vitro studies of peripheral blood mononuclear cells showed defective Fas-mediated apoptosis, and genomic sequencing identified a point mutation in the APT1 gene encoding Fas.

Dr. Michael C. Sneller (Laboratory of Immunoregulation, NIAID, NIH): Between 1990 and 1997, the NIH evaluated 45 patients under approved protocols for unexplained chronic lymphadenopathy, splenomegaly, or both. Among these patients, ALPS was subsequently diagnosed in 26 (12 male and 14 female). The remaining patients had some features of ALPS or had entirely different conditions. The Table shows the clinical and salient laboratory features of these 26 patients, of whom 23 had documented Fas mutations. The clinical and laboratory features of ALPS did not differ between patients who had mutations and those who did not. Clinical data on 9 of these patients are reported elsewhere (1, 6).

Table Jump PlaceholderTable.  Clinical and Immunologic Features in 26 Patients with the Autoimmune Lymphoproliferative Syndrome
Lymphoproliferative Disease

All 26 patients initially presented because of lymphadenopathy or splenomegaly at a median age of 11.5 months (range, 1 month to 9 years). Most had both splenomegaly and lymphadenopathy. Splenomegaly was frequently of massive proportions, and hepatomegaly was also common (Figure 1 G). Sixteen patients underwent splenectomy, most often for severe hypersplenism.

Lymphadenopathy was massive and distorted normal anatomic landmarks in some patients (Figure 1 A). Enlargement of abdominal and thoracic lymph nodes was frequently seen on computed tomography (Figure 1 F). Regardless of its extent, lymphadenopathy persisted for 2 or more years in almost all patients.

Histopathologic analyses of lymph nodes from patients with ALPS show architectural preservation, florid reactive follicular hyperplasia, and marked paracortical expansion with immunoblasts and plasma cells (1, 6, 31) (Figure 1 B). The paracortical expansion may be extensive enough to suggest a diagnosis of immunoblastic lymphoma, with many cells expressing the Ki-67 antigen indicative of active proliferation (32). However, the tissues show no chromosomal abnormalities or evidence of clonality (31). Increased numbers of double-negative T cells are also seen in the paracortical region of lymph node tissue (Figures 1C, 1D, and 1E). This combination of follicular hyperplasia and paracortical expansion by a mixed polyclonal infiltrate containing double-negative T cells differentiates ALPS from other benign and malignant lymphoproliferative lesions.

Autoimmunity

Circulating autoantibodies, overt autoimmune disease, or both were found in 23 of the 26 patients. Potentially pathogenic autoantibodies were detected in 22 patients (Table) but were not always associated with disease. For example, the direct Coombs test detected antibodies to erythrocytes in 19 patients, but 6 of these patients had no evidence of hemolysis. At least one autoimmune disease was documented in 17 patients (Table) and was evident in 4 of the 17 at the time of initial presentation with lymphoid hyperplasia. In the remaining 13 patients, autoimmune disease developed 6 months to 17 years later, suggesting that the proportion of patients with autoimmune disease increases over time.

The most common autoimmune diseases were hemolytic anemia and ITP (Table). Nine patients had at least one episode of hemolysis during which hemoglobin levels decreased to less than 4.4 mmol/L (7 mg/dL). In seven of eight patients with ITP, platelet counts decreased to less than 20 × 109 cells/L. Five patients also had hemolytic anemia, either concomitantly with active ITP or as isolated episodes with normal platelet counts.

Neutropenia (absolute neutrophil count <1.0 × 106 cells/L) in six patients seemed to result from autoimmune mechanisms because it developed after splenectomy and in the setting of normal myeloid cellularity on bone marrow examination.

Several nonhematologic autoimmune diseases also occurred in this group of patients. One patient developed the Guillain-Barré syndrome. Of two patients with glomerulonephritis, one later developed ITP and autoimmune biliary disease (Figure 1 A). Thus, in ALPS, multiple autoimmune diseases involving different organ systems may occur over time in a single patient.

No patient developed opportunistic infections or other clinical evidence of immunodeficiency. However, five patients who had splenectomy developed Streptococcus pneumoniae septicemia, usually despite appropriate antibiotic and vaccine prophylaxis.

Immunologic Studies

The most prominent abnormalities seen with routine immunologic testing of these patients were T-cell and B-cell lymphocytosis, increased numbers of circulating double-negative T lymphocytes, and polyclonal hypergammaglobulinemia. The magnitude of these abnormalities varied (Table). Patients with the most severe lymphoid hyperplasia also had the most pronounced lymphocytosis, the largest numbers of double-negative T lymphocytes, and the highest serum immunoglobulin levels.

Treatment

Episodes of autoimmune hemolytic anemia and ITP usually required treatment with high doses of glucocorticosteroids (prednisone, ≥ 1 mg/kg of body weight per day). High-dose intravenous immunoglobulin was ineffective or produced only transient benefit with respect to ITP. Recurrent ITP was interrupted in several patients with the use of monthly pulses of dexamethasone, 4 to 6 mg/kg per day for 5 days. Recombinant granulocyte colony-stimulating factor produced sustained increases in neutrophil counts in two patients with ALPS who had neutropenia and recurrent infections.

On the basis of studies in lpr mice in which interleukin-2 and cyclosporine were effective, patient 2 received empirical trials of these agents (3334). Moreover, this patient and many other patients received prednisone or intravenous immunoglobulin for the treatment of autoimmune disease. These therapies afforded, at best, a transient decrease in the degree of lymphadenopathy (1, 6).

Prognosis

Because most of our patients have been followed for relatively short periods, we do not yet know the ultimate prognosis associated with ALPS. So far, none of our 26 patients has died. However, the major determinants of illness seem to be the severity of autoimmune disease and the occurrence of sepsis after splenectomy.

Some information on the long-term prognosis associated with ALPS can be gained by considering three of our patients who are now adults (6, 8). Their medical records show manifestations of ALPS in early childhood. One patient has persistent lymphadenopathy but is otherwise well at age 26 years. The second patient had splenectomy at age 2 years (13). Her lymphadenopathy resolved during adolescence, but she developed ITP at age 18 years and autoimmune neutropenia at age 32 years. Thus, patients with ALPS have a lifelong risk for autoimmune disease. The third patient developed Hodgkin disease at age 26 years. Of note, this patient's brother also had a Fas mutation, had clinical features of ALPS, and died of lymphoma (6). These cases suggest that Fas mutations that impair antigen-induced lymphocyte apoptosis may be associated with an increased risk for lymphoma.

Dr. Michael Lenardo (Laboratory of Immunology, NIAID, NIH): The striking phenotype of lymphocyte expansion in patients with ALPS led to the hypothesis that its underlying cause is a defect in apoptosis, which is a crucial regulatory mechanism in the immune system (35). Apoptosis is a process by which the body rids itself of unneeded or harmful cells. It is essential during embryonic development and is thought to be conserved in all multicellular organisms for the homeostatic control of adult tissues. The term apoptosis has been used to describe a series of morphologic changes in a cell that is programmed to die; these changes include condensation and cleavage of the nuclear chromatin; blebbing of the cell membrane; and, finally, fragmentation of the cell into small, membrane-bound “apoptotic bodies” (36). The cellular remnants show phosphatidylserine and other ligands that interact with receptors on the surface of phagocytic cells, allowing rapid engulfment and removal of the dead cell. Hence, apoptosis eliminates cells with little of the inflammatory reaction that typically accompanies traumatic or necrotic cell death.

In the immune system, apoptosis has important functions (37). During lymphocyte differentiation in the thymus and bone marrow, it eliminates cells that are strongly autoreactive. In the peripheral immune system, it counteracts the potential accumulation of mature lymphocytes.

When a resting T cell is stimulated, it proliferates in response to interleukin-2 or other cytokines. This renders it sensitive to apoptosis. The fate of the proliferating T cell depends on the amount of antigen encountered. A large amount of antigen induces the expression of death cytokines, including tumor necrosis factor (TNF), and members of the family of similar proteins and their receptors (38) (Figure 2). The chief member of this family involved in lymphocyte apoptosis is the Fas receptor and its ligand (FasL; CD95L) (39). The induction of apoptosis in dividing T cells prevents the overexpansion of activated cells in the face of persistent or recurrent antigen exposure. A different form of apoptosis occurs after the antigen has been eliminated and the immune response is waning. Production of proliferative cytokines, such as interleukin-2, decreases. Dividing cells that are no longer needed for a protective response undergo lymphokine-withdrawal apoptosis. Somehow, a small number of the activated cells escape apoptosis and persist as “memory” T cells.

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Figure 2.
Mediators of lymphocyte apoptosis.TNFR1

Spanning the cell membrane are Fas (CD95) and tumor necrosis factor 1 ( ) molecules. Each functions in homotrimers to bind ligands (Fas ligand and TNF, respectively) and trigger apoptosis. Cytoplasmic adapter molecules (FADD/MORT-1) bind the similar death domains of each receptor and then form complexes with caspase 8, which is cleaved to activate other caspase enzymes that ultimately mediate degradation of cellular DNA, cell death, and disintegration. FADD = Fas-associated death domain protein; FLICE/MACH 1 = FADD-like interleukin-1-converting enzyme/mediator of receptor-induced toxicity 1; NF-κB = nuclear factor-κB; RIP = receptor interacting protein; TRADD = TNF receptor-associated death domain protein; TRAF 2 = TNF receptor-associated factor 2.

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The Fas and TNF death receptors and homologous proteins are the principal cell surface receptors that induce apoptosis in mammals, thereby regulating the deletion of autoreactive thymocytes and principal mature peripheral T cells (29, 3940). The TNF receptors (TNFRs) and Fas share significant amino acid sequences and structural homology. The extracellular portions of these proteins are important for ligand binding. Their cytoplasmic portions contain “death domains” that bind cytoplasmic signaling proteins essential for inducing apoptosis (41) (Figure 2). After their respective ligands bind to them, three molecules of Fas or TNFRs assemble into complexes. The cytoplasmic portions of the Fas trimer attract a cytoplasmic adapter protein known as FADD (Fas-associated death domain) or MORT1 (mediator of receptor-induced toxicity), and the cytoplasmic tails of a TNFR bind adapter molecules known as TRADD (TNFR-associated death domain) and RIP (receptor-interacting protein) (4142). These latter proteins also harbor death domains, which enable the further recruitment of the apoptosis-inducing protease caspase 8 (4248). Caspases, including caspase 8, are cysteine-containing proteinases that cleave themselves at aspartate residues to generate highly active, mature enzymes that proteolytically process further proteases in a cascade. The last members of this cascade damage mitochondria and degrade chromosomal DNA.

To investigate the possibility that ALPS could be the result of altered lymphocyte apoptosis, it was necessary to test the efficiency with which apoptosis could be induced in our patients' lymphocytes. Patient cells were stimulated with interleukin-2 and then treated with an antibody directed at Fas. The percentage of cells killed in our patients was significantly lower than the percentage of cells killed in healthy controls (Figure 3).

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Figure 3.
Apoptosis after Fas (CD95) stimulation is impaired in patients with the autoimmune lymphoproliferative syndrome (ALPS).NormPt

Cell loss is the fraction of cycling T cells lost after 24 hours of Fas cross-linking by an agonistic monoclonal antibody. Shown are the results obtained by using cycling T cells from normal controls ( ) and seven unrelated patients with ALPS ( ).

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These data strongly suggested that defects in apoptosis were associated with ALPS and that the failure of apoptosis might result from abnormal function of the Fas receptor. It remained, then, to determine whether the gene encoding Fas is mutated in patients with ALPS.

Dr. Jennifer M. Puck (Immunologic Genetics Branch, National Human Genome Research Institute, NIH): Figure 4 shows the organization of the APT1 gene. It contains nine exons and has a genomic span of about 25 kb on human chromosome 10q23 (30). Exons 2 through 5 encode the extracellular domain of Fas. A transmembrane region is encoded in exon 6. Exon 9 encodes the death domain referred to in the preceding section. The Fas protein is expressed in the heart and liver as well as in B and T lymphocytes. Particularly high amounts are found in activated T cells.

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Figure 4.
The organization of theAPT1gene encoding Fas (CD95) (shown as numbered boxes separated by slashed lines indicating the intron sequences).CRDsItFrbp(2)APT1

The gray boxes covering exons 2 through 5 correspond to the extracellular cysteine-rich receptor domains ( ). The dark area of exon 9 is the cytoplasmic death-signaling domain. The localization and type of mutations in patients with the autoimmune lymphoproliferative syndrome are depicted above the exon drawing. The top line of symbols identifies the location of all published mutations from other research centers, including those in Italy ( ) and France ( ). The lower line of symbols depicts the mutations identified in National Institutes of Health patients. All of the mutations to date are single-nucleotide changes except for the 290-base pair ( ) homozygous deletion in exon 9 (Fr) found in a severely affected daughter of related parents . The region of the gene most often mutated is the intracellular death domain.

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To date, more than 40 patients with ALPS have been identified. APT1 gene mutations have been found in more than 21 families, some of which have more than one affected member (28). The localization and type of mutations in patients with ALPS are depicted in Figure 4. These mutations are not polymorphisms because they have not been detected in the screening of hundreds of unrelated healthy persons. All of the mutations to date are single-nucleotide changes except for the homozygous deletion found in a severely affected child of related French parents (2, 5) (Figure 4).

By far, the most common form of ALPS is that associated with heterozygous Fas mutations; ALPS is inherited in an autosomal dominant fashion. The region of the APT1 gene most often mutated is the death domain. These mutations are predicted to result in early termination (frameshift insertions and deletions; amino acid changes to stop codons) or in single amino-acid substitutions (missense mutations) that disrupt the three-dimensional structure of the death domain (44). In vitro transfection experiments proved that Fas proteins bearing death-domain mutations inhibit the function of normal Fas proteins. This explained why heterozygous Fas mutations behaved in an autosomal dominant manner (3). Because Fas molecules form trimeric complexes to signal apoptosis, we predicted that a single abnormal Fas molecule in these complexes would impair apoptosis. When we expressed both mutated and normal Fas proteins in cells, we found that mutant proteins strongly inhibited the transmission of a death signal by the normal, wild-type protein.

Studies of family members of patients with ALPS identified additional persons carrying the same APT1 mutations. Some were completely free of the symptoms and signs of ALPS, whereas others met all of the diagnostic criteria for ALPS (24, 78). Still other mutation-bearing relatives had some but not all of the features of ALPS, such as episodes of significant adenopathy or enlarged spleen but no autoimmune disease. For example, a kindred of 14 persons in four generations was followed for up to 25 years (8). Some members had histories of splenomegaly or other features of ALPS, but 11 of the 14 were shown to have a heterozygous mutation in the death domain of Fas (8) (Figure 5). All of the mutation-bearing members of this kindred had impaired lymphocyte apoptosis. Among those with clinical features of ALPS, lymphoproliferation tended to abate by adulthood. The only premature death in the family was due to sepsis after splenectomy in one boy; however, the occurrence of non-Hodgkin lymphoma in one person at age 50 years, as well as this person's development of ITP at age 23 years and hemolytic anemia at age 54 years, show the risk for malignancy and the unpredictable appearance of autoimmune complications.

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Figure 5.
A kindred of 11 persons in four generations with a mutation in the death domain of Fas.(8)

A spectrum of clinical presentations is seen among the affected family members; some exhibit lymphoproliferation, increased double-negative T cells, and autoimmunity. One member developed lymphoma. The squares represent males; the circles represent females; the arrow identifies the proband; and the slash identifies a family member who died. Reproduced with permission from Infante and colleagues .

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Evaluation of families such as this one indicate that additional genetic or environmental factors must interact with defects in apoptosis to engender overt lymphoproliferation and autoimmunity. Such modifying factors might include other proteins in the Fas apoptosis pathway or related pathways (Figure 2).

In contrast to patients with ALPS and Fas mutations, whom we designate as having ALPS type Ia, both children and adults have been found to have autoimmune disease, chronic lymphoproliferation, and defective apoptosis but no Fas mutation. Some of these persons have expanded numbers of double-negative T cells, as well, and therefore have been designated as having ALPS type Ib if they have a Fas ligand mutation or ALPS type II if no genetic defect has been uncovered (6, 4950). The early studies of ALPS suggest that defects in apoptosis pathway proteins other than Fas might contribute not only to some cases of ALPS but also to a wider variety of syndromes with autoimmunity, lymphoproliferation, and possibly malignancy.

In all, many gene products regulating lymphocyte signaling networks have been implicated in lymphoproliferation and autoimmunity; many of these could be exacerbated by an apoptosis impairment and therefore may also be candidates for second mutations in ALPS. Other factors, such as excessive synthesis of the cytokine interleukin-10, may also play roles in the genesis of autoimmunity.

Dr. Warren Strober (Mucosal Immunity Section, Laboratory of Clinical Investigation, NIAID, NIH): Patients with ALPS have a B- and T-cell lymphocytosis and increased levels of double-negative T cells (18) (Table 1). Many of the T cells bear the MHC class II (DR antigens) surface marker, reflecting previous activation and indicating abnormal persistence. Moreover, cells in tissues often express an acute activation marker, CD69; this suggests that abnormal lymphocyte proliferation also contributes to the peripheral and tissue lymphocyte expansion seen in ALPS, not just to the prolonged survival of resting T cells.

To help understand what might be driving the lymphocyte proliferation, we measured plasma levels of cytokines in patients with ALPS (51). Circulating levels of the regulatory cytokines interleukin-4, interferon-γ, and interleukin-2 and levels of the inflammatory cytokines TNF-α, interleukin-1b, and interleukin-6 were generally normal. In contrast, plasma interleukin-10 values were strikingly elevated in almost all patients with ALPS: The median value was 183 pg/mL in 24 patients with ALPS but was 0 pg/mL in healthy controls and in 121 patients with lymphoma, vasculitis, or other autoimmune or lymphoproliferative disorders. Minimal increases in interleukin-10 levels were described in another study of Hodgkin disease (52). Of interest, the median level of interleukin-10 in family members with Fas mutations was only 7 pg/mL. Given that they all manifested defective apoptosis, it is evident that a high interleukin-10 level is related more to the presence of ALPS than to abnormal apoptosis.

We next examined the capacity of lymphocytes in patients with ALPS to release various cytokines after stimulation in vitro (51). Previously activated DR+ CD4+ T cells from six patients produced 20-fold more interleukin-4 and 10-fold more interleukin-5 than did DR+ T cells from controls. In contrast, the same cells produced 2-fold to 4-fold less interferon-γ and interleukin-2 than did DR+ T cells from controls. The double-negative T cells from our patients proved to be relatively unresponsive to in vitro stimulation; this parallels the results of studies of double-negative cells in MLR/lpr mice (53). The origin of these cells in patients with ALPS is uncertain, although evidence in the mice indicates that these cells derive from CD8+ T cells that have lost the ability to express CD8 (54). These studies suggest that the double-negative T cells are not likely to be participating in immune responses in the development of the autoimmune problems in our patients.

Finally, we examined the ability of monocytes and macrophages from patients with ALPS to release various cytokines after stimulation in vitro. These cells from patients with ALPS produced, on average, 5-fold more interleukin-10 and substantially less interleukin-12 than control cells did. Because the monocyte-macrophage population is vastly expanded in ALPS as a result of the general lymphoid expansion, these studies strongly suggest that this population is a source of high interleukin-10 levels in patients with ALPS.

In asking how these combined data might shed light on the development of autoimmunity in ALPS, we should recall two basic principles. First, as Figure 6 shows, T-cell immune response patterns are classified as either T helper 1 (Th1) (driven by interleukin-12 and leading to interferon-γ and TNF-α release) or T helper 2 (Th2) (driven by interleukin-4 and leading to release of interleukin-4, interleukin-5, and interleukin-6). Second, many immunologic disorders are associated with imbalanced Th1 or Th2 responses. Thus, in patients with multiple sclerosis or Crohn disease and mice with similar diseases, greatly upregulated Th1 activity leads to inflammation (5558). Conversely, in patients with systemic lupus erythematosus or allergic asthma, unbridled Th2 responses underlie inflammation and autoimmunity (5963). Thus, the finding that the T cells of patients with ALPS show a pronounced Th2 profile begins to explain the humoral autoimmunity seen in ALPS; the Th2 cytokines provide the T-cell drive to B cells needed to produce autoantibodies.

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Figure 6.
Proposed mechanism of autoimmunity in the autoimmune lymphoproliferative syndrome. Top.BTAPCBottom.IL

In normal persons, B-cell ( ) and T-cell ( ) precursors undergo development under conditions that lead to the elimination of self-reactive cells. In the context of antigen stimulation, the mature B and T cells that emerge intact from this process interact through CD40/CD40L, and the B cells differentiate into antibody-producing cells ( ). As a further safeguard against the development of self-reactive cells, the latter are susceptible to Fas-mediated apoptosis unless they are co-stimulated by specific antigen. Interleukin ( )-10 overproduction induces intracellular antiapoptotic proteins (Bcl-2 family proteins); this increases the risk that self-reactive cells will persist during B-cell and T-cell development. This problem is compounded by defective Fas-mediated apoptosis of mature cells. The result is the expansion of self-reactive cells that mediate autoimmunity.

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The occurrence of a Th2 bias in ALPS is probably due to both elevated interleukin-10 production and decreased interleukin-12 production. Interleukin-10 inhibits interleukin-12 production and thus drives T-cell differentiation in the direction of Th2 responses (57, 64). It has been claimed that increased interleukin-10 production accounts for the reduced interleukin-12 levels seen in patients with systemic lupus erythematosus (60, 65). In ALPS, defective Fas-mediated apoptosis cannot be the sole basis of the interleukin-10 elevation because healthy relatives with Fas mutations do not have it. It is more likely that elevated interleukin-10 production is an independent abnormality.

Increased interleukin-10 production may have additional effects on B-cell and T-cell survival. Interleukin-10 induces the antiapoptotic protein Bcl-2 in both B cells and T cells and thus retards their death (6668). Therefore, overexpression of interleukin-10 could lead to the persistence of autoreactive cell clones and even malignant cell clones. Together, these contribute to the clinical features and complications of ALPS.

The autoimmune lymphoproliferative syndrome is a newly recognized disorder caused by inherited defects in the mechanisms that induce lymphocytes to die. It permits the accumulation of lymphocytes in and the expansion of lymphoid organs. Some of the surviving lymphocytes react with a patient's own antigens, precipitating autoimmunity. This syndrome is the first known human disorder of these cell death pathways and is a novel genetic cause of autoimmune disease.

Apoptosis: A tightly regulated program of molecular and biochemical processes that leads to cell death.

Exon: A coding section of a gene retained in the gene's messenger RNA that is translated into a segment of protein.

Fas: A lymphocyte surface receptor protein that initiates apoptosis.

Intron: An intervening RNA segment that is spliced out of a gene's messenger RNA.

T helper 1: CD4+ cells that produce interleukin-2 and interferon-γ, which promote cellular immunity.

T helper 2: CD4+ cells that produce interleukin-4, which promotes humoral immunity.

Transcription: The making of an RNA molecule by using the information encoded in DNA.

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CrossRef
 
Holiman JL, Madge GE.  A familial disorder characterized by hepatosplenomegaly presenting as “preleukemia.”. Va Med Mon. 1971; 98.644-8
 
Rao LM, Shahidi NT, Opitz JM.  Hereditary splenomegaly with hypersplenism. Clin Genet. 1974; 5.379-86
 
Hess AF.  The blood and blood vessels in hemophilia and other hemorrhagic diseases. Arch Intern Med. 1916; 17.203-20
 
Dameshek W, Schwartz SO.  Hemolysins as the cause of clinical and experimental hemolytic anemias. with particular reference to the nature of spherocytosis and increased fragility. Am J Med Sci. 1938; 196.769-92
CrossRef
 
Evans RS, Takahashi K, Duane RT, Payne R, Liu CK.  Primary thrombocytopenic purpura and acquired hemolytic anemia. Evidence for a common etiology. Ann Intern Med. 1951; 87.48-65
CrossRef
 
Hennemann VH, Krause H.  Chronische Trombozytopenie (Morbus Werlhof) und erworbene hämolytische Anämie bei zwei Schwestern. [Chronic thrombocytopenia (Werlhof's disease) and acquired hemoloytic anemia in two sisters.]. Dtsche Med Wochenschr. 1964; 89.1161-6
CrossRef
 
Harms D, Sachs V.  Familial chronic thrombocytopenia with platelet autoantibodies. Acta Haematol. 1965; 34.30-5
CrossRef
 
Seip M, Harboe M, Cyvin K.  Chronic autoimmune hemolytic anemia in childhood with cold antibodies, aplastic crises, and familial occurrence. Acta Paediatr Scand. 1969; 58.275-80
CrossRef
 
Dacie J.  The Haemolytic Anemias. Vol. 3. New York: Churchill Livingstone; 1992.
 
Dale DC.  Lymphadenopathy and lymphoproliferative disorders. Immunology and Allergy Clinics of North America. 1993; 13.359-69
 
Canale VC, Smith CH.  Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr. 1967; 70.891-9
CrossRef
 
Weisdorf SA, Krivit W.  Paucity of splenic germinal centers: a new and unique splenomegaly syndrome including dysfunctional immune system. Clin Immunol Immunopathol. 1982; 23.492-500
CrossRef
 
Horowitz SD, Borcherding W, Hong R.  Autoimmune hemolytic anemia as a manifestation of T-suppressor-cell deficiency. Clin Immunol Immunopathol. 1984; 33.313-23
CrossRef
 
McKinley R, Kwan YL, Lam-po-Tang PR.  Familial splenomegaly syndrome with reduced circulating T helper cells and splenic germinal centre hypoplasia. Br J Haematol. 1987; 67.393-6
CrossRef
 
Theofilopoulos AN, Dixon FJ.  Murine models of systemic lupus erythematosus. Adv Immunol. 1985; 37.269-390
 
Cohen PL, Eisenberg RA.  Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991; 9.243-69
CrossRef
 
Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, et al..  Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989; 245.301-5
CrossRef
 
Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S.  Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992; 356.314-8
CrossRef
 
Behrmann I, Walczak H, Krammer PH.  Structure of the human APO-1 gene. Eur J Immunol. 1994; 24.3057-62
CrossRef
 
Lim MS, Straus SE, Dale JK, Fleisher TA, Stetler-Stevenson M, Strober W, et al..  Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol. 1998; 153.1541-50
CrossRef
 
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984; 133.1710-5
 
Mountz JD, Smith HR, Wilder RL, Reeves JP, Steinberg AD.  CS-A therapy in MRL- lpr/lpr mice: amelioration of immunopathology despite autoantibody production. J Immunol. 1987; 138.157-63
 
Gutierrez JC, Andreu JL, Revilla Y, Vinuela E, Martinez C.  Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature. 1990; 346.271-4
CrossRef
 
Lenardo MJ.  Fas and the art of lymphocyte maintenance. J Exp Med. 1996; 183.721-4
CrossRef
 
Cohen JJ, Duke RC, Fadok VA, Sellins KS.  Apoptosis and programmed cell death in immunity. Ann Rev Immunol. 1992; 10.267-93
CrossRef
 
Lenardo MJ.  The molecular regulation of lymphocyte apoptosis. Semin Immunol. 1997; 9.1-5
CrossRef
 
Smith CA, Farrah T, Goodwin RG.  The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994; 76.959-66
CrossRef
 
Nagata S, Golstein P.  The Fas death factor. Science. 1995; 267.1449-56
CrossRef
 
Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ.  Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995; 377.348-51
CrossRef
 
Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, et al..  Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995; 14.5579-88
 
Boldin MP, Goncharov TM, Goltsev YV, Wallach D.  Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/Apo-1- and TNF receptor-induced cell death. Cell. 1996; 85.803-15
CrossRef
 
Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry HA, Wong WW, et al..  Human ICE/CED-3 protease nomenclature [Letter]. Cell. 1996; 87.171
CrossRef
 
Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW.  NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature. 1996; 384.638-41
CrossRef
 
Enari M, Hug H, Nagata S.  Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature. 1995; 375.78-81
CrossRef
 
Los M, Van de Craen M, Penning LC, Schenk H, Westendorp M, Baeuerle PA, et al..  Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis. Nature. 1995; 375.81-3
CrossRef
 
Chinnaiyan AM, O'Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, et al..  Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science. 1996; 274.990-2
CrossRef
 
Chinnaiyan AM, Dixit VM.  Portrait of an executioner: the molecular mechanism of FAS/APO-1-induced apoptosis. Semin Immunol. 1997; 9.69-76
CrossRef
 
Dianzani U, Bragardo M, DiFranco D, Alliaudi C, Scagni P, Buonfiglio D, et al..  Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Blood. 1997; 89.2871-9
 
Wu J, Wilson J, He J, Xiang L, Schur PH, Mountz JD.  Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest. 1996; 98.1107-13
CrossRef
 
Fuss IJ, Strober W, Dale JK, Fritz S, Pearlstein GR, Puck JM, et al..  Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humor autoimmunity. J Immunol. 1997; 158.1912-8
 
Sarris AH, Kliche KO, Peethambaram PP, Witzig T, Andreeff M, Cabanillas F.  Interleukin-10 as a prognostic factor for Hodgkin's disease treated with ABVD: results from MD Anderson and Mayo Clinic [Abstract]. Blood. 1997; 90.335a
 
Giese T, Allison JP, Davidson WF.  Functionally anergic lpr and gld B220+ T cell receptor (TCR)alpha/beta double-negative T cells express CD28 and respond to costimulation with phorbol myristate acetate and antibodies to CD28 and the TCR. J Immunol. 1993; 151.597-609
 
Giese T, Davidson WF.  Chronic treatment of C3H-lpr/lpr and C3H gld/gld mice with anti-CD8 monoclonal antibody prevents the accumulation of double negative T cells but not autoantibody production. J Immunol. 1994; 152.2000-10
 
Ferrante P, Fusi ML, Sarasella M, Caputo D, Biasin M, Trabattoni D, et al..  Cytokine production and surface marker expression in acute and stable multiple sclerosis: altered IL-12 production and augmented signaling lymphocytic activation molecule (SLAM)-expressing lymphocytes in acute multiple sclerosis. J Immunol. 1998; 160.1514-21
 
Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, et al..  Disparate CD4+ lamina propria (LP) lymphocyte secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-γ whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996; 157.1261-70
 
Segal BM, Dwyer BK, Shevach EM.  An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med. 1998; 187.537-46
CrossRef
 
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W.  Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995; 182.1281-90
CrossRef
 
Horwitz DA, Gray JD, Behrendsen SC, Kubin M, Rengaraju M, Ohtsuka K, et al..  Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosus. Arthritis Rheum. 1998; 41.838-44
CrossRef
 
Liu TF, Jones BM.  Impaired production of IL-12 in systemic lupus erythematosus. II: IL-12 production in vitro is correlated negatively with serum IL-10, positively with serum IFN-γ and negatively with disease activity in SLE. Cytokine. 1998; 10.148-53
CrossRef
 
Segal R, Bermas BL, Dayan M, Kalush F, Shearer G, Mozes E.  Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease. J Immunol. 1997; 158.3009-16
 
Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, Durham SR.  Activation of CD4+ T cells, increased TH2-type cytokines, mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol. 1993; 92.213-34
 
Tanaka H, Nagai H, Maeda Y.  Effect of anti-IL-4 and anti-IL-5 antibodies on allergy airway hyperresponsiveness in mice. Life Sci. 1994; 62:PL169-74.
 
Moore KW, O'Garra A, de Waal Malefyt R, Veiera P, Mosmann T.  Interleukin-10. Annu Rev Immunol. 1993; 11.165-90
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Mongan A, Ramdahin S, Warrington RJ.  Interleukin-10 response abnormalities in systemic lupus erythematosus. Scand J Immunol. 1997; 46.406-12
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Levy Y, Brouet JC.  Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bc1-2 protein. J Clin Invest. 1994; 93.424-8
CrossRef
 
Li L, Krajewski S, Reed JC, Choi YS.  The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mc1-1 expression. Cell Immunol. 1997; 178.33-41
CrossRef
 
Cohen SB, Crawley JB, Kahan MC, Feldmann M, Foxwell BM.  Interleukin-10 rescues T cells from apoptotic cell death: association with an upregulation of Bcl-2. Immunology. 1997; 92.1-5
CrossRef
 

Figures

Grahic Jump Location
Figure 1.
Clinical, radiologic, and histologic features of patients with the autoimmune lymphoproliferative syndrome. A.[6]B.C.D.E.++F.G.

Frontal view of National Institutes of Health patient 2. (Reproduced with permission from Sneller and colleagues .) Lymph node from patient 2 showing follicular hyperplasia and plasmacytosis (hematoxylin and eosin). (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD3. (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD4. (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD8. Few of the cells that stain reddish brown for CD3 are CD4 or CD8 . (Courtesy of Dr. Elaine Jaffe.) Computed tomographic scan through the upper thorax and axillae and abdomen of patient 23 showing marked paratracheal, anterior mediastinal, and axillary adenopathy. (Courtesy of Dr. Nilo Avila.) Computed tomographic scan through the upper thorax and axillae and abdomen of patient 23 showing hepatosplenomegaly. (Courtesy of Dr. Nilo Avila.) For panels B to E, original magnifications were ×200. For panels C to E, the stain used was immunoperoxidase.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Mediators of lymphocyte apoptosis.TNFR1

Spanning the cell membrane are Fas (CD95) and tumor necrosis factor 1 ( ) molecules. Each functions in homotrimers to bind ligands (Fas ligand and TNF, respectively) and trigger apoptosis. Cytoplasmic adapter molecules (FADD/MORT-1) bind the similar death domains of each receptor and then form complexes with caspase 8, which is cleaved to activate other caspase enzymes that ultimately mediate degradation of cellular DNA, cell death, and disintegration. FADD = Fas-associated death domain protein; FLICE/MACH 1 = FADD-like interleukin-1-converting enzyme/mediator of receptor-induced toxicity 1; NF-κB = nuclear factor-κB; RIP = receptor interacting protein; TRADD = TNF receptor-associated death domain protein; TRAF 2 = TNF receptor-associated factor 2.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Apoptosis after Fas (CD95) stimulation is impaired in patients with the autoimmune lymphoproliferative syndrome (ALPS).NormPt

Cell loss is the fraction of cycling T cells lost after 24 hours of Fas cross-linking by an agonistic monoclonal antibody. Shown are the results obtained by using cycling T cells from normal controls ( ) and seven unrelated patients with ALPS ( ).

Grahic Jump Location
Grahic Jump Location
Figure 4.
The organization of theAPT1gene encoding Fas (CD95) (shown as numbered boxes separated by slashed lines indicating the intron sequences).CRDsItFrbp(2)APT1

The gray boxes covering exons 2 through 5 correspond to the extracellular cysteine-rich receptor domains ( ). The dark area of exon 9 is the cytoplasmic death-signaling domain. The localization and type of mutations in patients with the autoimmune lymphoproliferative syndrome are depicted above the exon drawing. The top line of symbols identifies the location of all published mutations from other research centers, including those in Italy ( ) and France ( ). The lower line of symbols depicts the mutations identified in National Institutes of Health patients. All of the mutations to date are single-nucleotide changes except for the 290-base pair ( ) homozygous deletion in exon 9 (Fr) found in a severely affected daughter of related parents . The region of the gene most often mutated is the intracellular death domain.

Grahic Jump Location
Grahic Jump Location
Figure 5.
A kindred of 11 persons in four generations with a mutation in the death domain of Fas.(8)

A spectrum of clinical presentations is seen among the affected family members; some exhibit lymphoproliferation, increased double-negative T cells, and autoimmunity. One member developed lymphoma. The squares represent males; the circles represent females; the arrow identifies the proband; and the slash identifies a family member who died. Reproduced with permission from Infante and colleagues .

Grahic Jump Location
Grahic Jump Location
Figure 6.
Proposed mechanism of autoimmunity in the autoimmune lymphoproliferative syndrome. Top.BTAPCBottom.IL

In normal persons, B-cell ( ) and T-cell ( ) precursors undergo development under conditions that lead to the elimination of self-reactive cells. In the context of antigen stimulation, the mature B and T cells that emerge intact from this process interact through CD40/CD40L, and the B cells differentiate into antibody-producing cells ( ). As a further safeguard against the development of self-reactive cells, the latter are susceptible to Fas-mediated apoptosis unless they are co-stimulated by specific antigen. Interleukin ( )-10 overproduction induces intracellular antiapoptotic proteins (Bcl-2 family proteins); this increases the risk that self-reactive cells will persist during B-cell and T-cell development. This problem is compounded by defective Fas-mediated apoptosis of mature cells. The result is the expansion of self-reactive cells that mediate autoimmunity.

Grahic Jump Location

Tables

Table Jump PlaceholderTable.  Clinical and Immunologic Features in 26 Patients with the Autoimmune Lymphoproliferative Syndrome

References

Sneller MC, Straus SE, Jaffe ES, Jaffe JS, Fleisher TA, Stetler-Stevenson M, et al..  A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest. 1992; 90.334-41
CrossRef
 
Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, et al..  Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995; 268.1347-9
CrossRef
 
Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, et al..  Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995; 81.935-46
CrossRef
 
Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB.  Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med. 1996; 335.1643-9
CrossRef
 
Le Deist F, Emile JF, Rieux-Laucat F, Benkerrou M, Roberts I, Brousse N, et al..  Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet. 1996; 348.719-23
CrossRef
 
Sneller MC, Wang J, Dale JK, Strober W, Middleton LA, Choi Y, et al..  Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. 1997; 89.1341-8
 
Bettinardi A, Brugnoni D, Quiròs-Roldan E, Malagoli A, La Grutta S, Correra A, et al..  Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood. 1997; 89.902-9
 
Infante AJ, Britton HA, DeNapoli T, Middleton LA, Lenardo MJ, Jackson CE, et al..  The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome due to a Fas mutation that impairs lymphocyte apoptosis. J Pediatr. 1998; 133.629-33
CrossRef
 
Wilson C.  Some cases showing hereditary enlargement of the spleen. Transactions of the Clinical Society. 1890; 23.16-172
 
Randall DL, Reiquam WC, Githens JH, Robinson A.  Familial myeloproliferative disease. Am J Dis Child. 1965; 110.479-500
 
Darte JM, McClure PD, Saunders EF, Weber J, Donohue WL.  Congenital lymphoid hyperplasia with persistent hyperlymphocytosis. N Engl J Med. 1971; 284.431-2
CrossRef
 
Holiman JL, Madge GE.  A familial disorder characterized by hepatosplenomegaly presenting as “preleukemia.”. Va Med Mon. 1971; 98.644-8
 
Rao LM, Shahidi NT, Opitz JM.  Hereditary splenomegaly with hypersplenism. Clin Genet. 1974; 5.379-86
 
Hess AF.  The blood and blood vessels in hemophilia and other hemorrhagic diseases. Arch Intern Med. 1916; 17.203-20
 
Dameshek W, Schwartz SO.  Hemolysins as the cause of clinical and experimental hemolytic anemias. with particular reference to the nature of spherocytosis and increased fragility. Am J Med Sci. 1938; 196.769-92
CrossRef
 
Evans RS, Takahashi K, Duane RT, Payne R, Liu CK.  Primary thrombocytopenic purpura and acquired hemolytic anemia. Evidence for a common etiology. Ann Intern Med. 1951; 87.48-65
CrossRef
 
Hennemann VH, Krause H.  Chronische Trombozytopenie (Morbus Werlhof) und erworbene hämolytische Anämie bei zwei Schwestern. [Chronic thrombocytopenia (Werlhof's disease) and acquired hemoloytic anemia in two sisters.]. Dtsche Med Wochenschr. 1964; 89.1161-6
CrossRef
 
Harms D, Sachs V.  Familial chronic thrombocytopenia with platelet autoantibodies. Acta Haematol. 1965; 34.30-5
CrossRef
 
Seip M, Harboe M, Cyvin K.  Chronic autoimmune hemolytic anemia in childhood with cold antibodies, aplastic crises, and familial occurrence. Acta Paediatr Scand. 1969; 58.275-80
CrossRef
 
Dacie J.  The Haemolytic Anemias. Vol. 3. New York: Churchill Livingstone; 1992.
 
Dale DC.  Lymphadenopathy and lymphoproliferative disorders. Immunology and Allergy Clinics of North America. 1993; 13.359-69
 
Canale VC, Smith CH.  Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr. 1967; 70.891-9
CrossRef
 
Weisdorf SA, Krivit W.  Paucity of splenic germinal centers: a new and unique splenomegaly syndrome including dysfunctional immune system. Clin Immunol Immunopathol. 1982; 23.492-500
CrossRef
 
Horowitz SD, Borcherding W, Hong R.  Autoimmune hemolytic anemia as a manifestation of T-suppressor-cell deficiency. Clin Immunol Immunopathol. 1984; 33.313-23
CrossRef
 
McKinley R, Kwan YL, Lam-po-Tang PR.  Familial splenomegaly syndrome with reduced circulating T helper cells and splenic germinal centre hypoplasia. Br J Haematol. 1987; 67.393-6
CrossRef
 
Theofilopoulos AN, Dixon FJ.  Murine models of systemic lupus erythematosus. Adv Immunol. 1985; 37.269-390
 
Cohen PL, Eisenberg RA.  Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991; 9.243-69
CrossRef
 
Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, et al..  Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989; 245.301-5
CrossRef
 
Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S.  Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992; 356.314-8
CrossRef
 
Behrmann I, Walczak H, Krammer PH.  Structure of the human APO-1 gene. Eur J Immunol. 1994; 24.3057-62
CrossRef
 
Lim MS, Straus SE, Dale JK, Fleisher TA, Stetler-Stevenson M, Strober W, et al..  Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol. 1998; 153.1541-50
CrossRef
 
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984; 133.1710-5
 
Mountz JD, Smith HR, Wilder RL, Reeves JP, Steinberg AD.  CS-A therapy in MRL- lpr/lpr mice: amelioration of immunopathology despite autoantibody production. J Immunol. 1987; 138.157-63
 
Gutierrez JC, Andreu JL, Revilla Y, Vinuela E, Martinez C.  Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature. 1990; 346.271-4
CrossRef
 
Lenardo MJ.  Fas and the art of lymphocyte maintenance. J Exp Med. 1996; 183.721-4
CrossRef
 
Cohen JJ, Duke RC, Fadok VA, Sellins KS.  Apoptosis and programmed cell death in immunity. Ann Rev Immunol. 1992; 10.267-93
CrossRef
 
Lenardo MJ.  The molecular regulation of lymphocyte apoptosis. Semin Immunol. 1997; 9.1-5
CrossRef
 
Smith CA, Farrah T, Goodwin RG.  The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994; 76.959-66
CrossRef
 
Nagata S, Golstein P.  The Fas death factor. Science. 1995; 267.1449-56
CrossRef
 
Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ.  Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995; 377.348-51
CrossRef
 
Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, et al..  Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995; 14.5579-88
 
Boldin MP, Goncharov TM, Goltsev YV, Wallach D.  Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/Apo-1- and TNF receptor-induced cell death. Cell. 1996; 85.803-15
CrossRef
 
Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry HA, Wong WW, et al..  Human ICE/CED-3 protease nomenclature [Letter]. Cell. 1996; 87.171
CrossRef
 
Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW.  NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature. 1996; 384.638-41
CrossRef
 
Enari M, Hug H, Nagata S.  Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature. 1995; 375.78-81
CrossRef
 
Los M, Van de Craen M, Penning LC, Schenk H, Westendorp M, Baeuerle PA, et al..  Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis. Nature. 1995; 375.81-3
CrossRef
 
Chinnaiyan AM, O'Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, et al..  Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science. 1996; 274.990-2
CrossRef
 
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Sarris AH, Kliche KO, Peethambaram PP, Witzig T, Andreeff M, Cabanillas F.  Interleukin-10 as a prognostic factor for Hodgkin's disease treated with ABVD: results from MD Anderson and Mayo Clinic [Abstract]. Blood. 1997; 90.335a
 
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