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IMMUNOBIOLOGY
From the Immunology Service, Department of Laboratory
Medicine, Clinical Center, Laboratory of Clinical Investigation and
Laboratory of Immunology, National Institute of Allergy and Infectious
Diseases, and the Genetics and Molecular Biology Branch, National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD.
Autoimmune lymphoproliferative syndrome (ALPS) type Ia
is caused by inherited defects in apoptosis and is characterized by nonmalignant lymphoaccumulation, autoimmunity, and increased
Apoptosis plays an important role in the
homeostasis of mature lymphocytes. T-cell apoptosis is achieved by both
active (antigen-driven) and passive pathways. An integral feature of
the active pathway is the expression of the cell surface receptor Fas
(CD95/APO-1), which on interaction with its ligand, FasL, induces
lymphocyte apoptosis.1
The importance of apoptosis in the maintenance of lymphocyte
homeostasis is illustrated by genetic defects of Fas and FasL in both
mice and humans. In mice, genetic defects in the TNFRSF6 gene encoding Fas and TNFSF6 gene encoding FasL genes cause
the lpr and gld phenotypes, respectively,
which are characterized by lymphoproliferation, autoantibody formation
with autoimmune manifestations, and increased T-cell receptor
(TcR)- The majority of patients with ALPS have inherited heterozygous
mutations in the TNFRSF6 gene (formerly known as
APT1), which encodes Fas. These patients are designated as
ALPS type Ia. Among the patients with ALPS who lack TNFRSF6
mutations are patients with mutations in the TNFSF6
gene, encoding FasL (ALPS type Ib), or in the CASP10 gene,
encoding caspase 10 (ALPS type II).13-15 The remainder of
patients have defects that are yet to be identified (provisionally
referred to as ALPS type III).16,17 Although every person
carrying a TNFRSF6 mutation has defective lymphocyte apoptosis in vitro, the variable penetrance of other ALPS features has
indicated that factors other than a mutation in a component of the Fas
pathway are required for the full clinical expression of ALPS, or,
alternatively, that protective factors are present preventing
expression of ALPS manifestations.10,18
In this study we report the immunophenotypic features of 166 members of
31 families with ALPS type Ia, and of 12 patients with ALPS type II or
III. The results provide a comprehensive immunophenotypic picture of
ALPS and support the conclusion that certain alterations in lymphocyte
subsets or their causal factors or both are associated with clinical disease.
Study population
Flow cytometry
Detection of Fas-mediated apoptosis in vitro Apoptosis assays were performed on Epstein-Barr virus (EBV)-transformed B lymphocytes as previously described.7 Apoptosis was induced with 500 to 1000 mg/mL APO-1 anti-Fas antibody with protein A added for maximal receptor cross-linking. Family members were analyzed on the same day with the same concentrations of APO-1, and maximally normalized percent cell loss was calculated by dividing the actual cell loss from the most effective dose of APO-1 by the percent cell loss of normal control EBV cell lines (a minimum of 2/experiment). Averages and SDs were calculated using Graphpad Prism software (Graphpad, San Diego, CA).Statistical analysis For unpaired comparisons of lymphocyte subsets, the nonparametric Mann-Whitney U test was used. All P values are 2-tailed and are regarded as statistically significant if P < .05. In addition, Spearman rank correlation coefficients were calculated for correlation analysis of age and lymphocyte markers. For the apoptosis experiments, pairwise t tests were used, and P values <.05 were regarded significant.
Demographic features Demographic features of the study population are shown in Table 1. The male-to-female ratio was 1.8:1 for the proband Ia group, 1:1 for the M+/A+ group, 0.8:1 for the M+/A
group, 1:1 for the M/A group, and 1.8:1 for the proband II/III
group. As is clear from Table 1, the age of the individuals in the
proband Ia and proband II/III group was lower than the other 3 groups. Not shown, all subjects with TNFRSF6 mutations (M+) had
defective in vitro lymphocyte apoptosis.
Immunophenotypic profiles of lymphocyte subsets Absolute numbers of lymphocyte subsets and the percentage expression of the lymphocyte markers are presented in Table 2. To determine if specific immunophenotypic profiles distinguished each group, absolute numbers of lymphocyte subsets were compared between the proband Ia, M+/A+, M+/A,
and M/A groups and the HC group (Table 2), and between the family
groups with or without a diagnosis of ALPS and with different Fas
mutation status (Table 3). When compared
to unrelated controls, the members of the proband Ia and M+/A+ groups
demonstrated significant expansions of CD3+ T cells,
CD8+ T cells, DNT cells expressing TcR- / , DNT cells
expressing TcR- / , CD8+/CD57+ T cells, and
total B cells, as well as B cells coexpressing CD5. However, these 2 groups showed no expansion of CD4+ T cells or NK cells.
When the group of TNFRSF6 mutation-positive, ALPS-negative
family members (M+/A) was compared to the HC group, statistically
significant alterations were confined to an expansion of
CD8+ T cells and both DNT cell subsets. The M/A group
revealed a small increase in the number of CD3+ T cells,
CD8+ T cells, both DNT cell subsets, and CD5+ B
cells, all of which were statistically significant. The increase in the
absolute number of /+-DNT cells in this group was
reflective of the entire group because 70% of subjects in the M/A
group had an absolute number of /+-DNT cells that was
greater than the median number of /+-DNT cells in the
HC group (and in one third of the M/A group, this was greater than
the 90th percentile of the HC group).
Next, absolute numbers of lymphocyte subsets were compared between the
ALPS Ia family groups (Table 3). ALPS Ia probands had significantly
higher numbers of Immunophenotypic profiles of T-cell activation markers Absolute numbers and the percentage of T cells expressing the activation markers HLA-DR and CD25 were compared between the various groups (Tables 2 and 3). There was a significant increase in the expression of HLA-DR on T cells in both the proband Ia and M+/A+ groups. Both groups also displayed a decrease in CD25+ T cells, but only in the proband Ia group did this reach statistical significance. These findings were not observed in either the M+/A or
M/A groups. There was no statistical difference between the proband
Ia and M+/A+ groups when comparing T-cell HLA-DR and CD25 expression on
T cells. Spearman rank correlation coefficients revealed no correlation
between the absolute numbers of CD3+/HLA-DR+
and CD3+/CD25+ T cells in members of the
proband Ia and M+/A+ groups (data not shown), indicating that increased
HLA-DR expression occurred independently of decreased CD25 expression.
To further illustrate these opposite and independent immunophenotypic
findings, a
CD3+/CD25+-to-CD3+/HLA-DR+
ratio was generated, the results of which are shown in Figure 1A. In healthy controls the median value
of this ratio was 3.0 and this was not significantly different in the
M+/A (2.2) and M/A (2.3) groups. However, in the proband Ia and
M+/A+ groups the ratio was significantly lower than the HC group,
having a median value of 0.3 (P < .0001) and 0.9 (P < .0001), respectively. The ratio was significantly
lower in the proband Ia group as compared to the M+/A+ group, and the
ratio in the M+/A+ group was significantly lower than the ratio in the
M+/A group. The difference between the ratios in the M+/A and
M/A groups was not statistically significant.
The decrease in CD3+/CD25+ was further
explored in the proband Ia group, the group with a significantly lower
number of CD3+/CD25+ cells and the lowest
CD3+/CD25+-to-CD3+/HLA-DR+
ratio, and in the M+/A+ group. Results regarding CD25 expression on
CD4+ T cells and CD8+ T cells were available in
26 of 31 members of the proband Ia and 17 of 28 members of the M+/A+
group. It revealed that, although there was no difference in the
percentage of CD25 Comparisons between ALPS type Ia and ALPS type II/III probands In addition to the 31 probands with ALPS type Ia, lymphocyte subsets were also evaluated in 2 probands with ALPS type II and 9 probands with ALPS type III (proband II/III group). Median cell numbers and percentages are shown in Table 2, and absolute numbers of lymphocyte subsets were compared between the proband II/III group and the HC group (Table 2). This showed a significant increase in CD3+ T cells, CD8+ T cells, both DNT cell subsets, CD8+/CD57+ T cells, and total B cells, including B cells expressing CD5 in the proband II/III group (Table 2). There was a significant increase in CD3+/HLA-DR+ T cells and a decrease in CD3+/CD25+ T cells. Although the number of most lymphocyte subsets was higher in the proband Ia group than in the proband II/III group, this difference did not reach statistical significance for any subset (Table 3). The CD3+/CD25+-to-CD3+/HLA-DR+ ratio in the proband II/III group (median of 0.4) was, similar to the proband Ia group, also significantly lower than the HC group (P < .0001).The influence of age on immunophenotypic findings It is well known that distribution of certain lymphocyte populations depend on the individual's age.20 Table 1 shows that the mean and median age of the individuals in the proband Ia group (and the proband II/III group) was lower than that of the other groups (including the HC group). Two approaches were used to ascertain if immunophenotypic alterations were influenced by age. First, the proband Ia group was divided in 2 groups, based on age. Comparing the absolute numbers of the lymphocyte subsets did not reveal significant changes between younger probands (n = 16; median age = 7) versus older probands (n = 15; median age = 16), with the exception of increased/+-DNT cells in the younger probands. This
was also the only T-cell subset that was significantly increased
compared to the M+/A+ group (median age = 28; Table 3). In addition,
Spearman rank correlation coefficients were calculated. This analysis
revealed no correlation between age and the major T-cell changes
including the increase in /+-DNT cells and B-cell
alterations in the proband group or in the M+/A+ group, which also
consisted of younger individuals.
Second, because it has been appreciated that certain ALPS
manifestations tend to decrease over time, the possibility that the
magnitude of immunophenotypic findings reflects age-related changes
stemming from the "natural history" of ALPS was evaluated. To this
effect, 7 probands who were studied at least 4 times over a 3- to
8-year period were identified. First and last available numbers of
Relationship between immunophenotype and ALPS features Although the family members in the M+/A group did not fulfill
all ALPS case criteria, specific ALPS features, in addition to
defective apoptosis, that are part of those criteria were present in 25 of 42 individuals in this group. To determine if there was a
relationship between the presence of more ALPS features and abnormal
immunophenotypic findings, the individuals in the M+/A group were
assigned to groups based on the number of ALPS features documented in
their medical records. Features included lymphadenopathy/splenomegaly, 1% or more /+-DNT cells, autoantibodies, and
autoimmunity. Twenty subjects in the M+/A group showed one ALPS
feature, 16 of 20 having 1% or more /+-DNT cells and
4 of 20 demonstrating autoantibodies. An additional 4 subjects in this
group had 1% or more /+-DNT cells together with the
presence of circulating autoantibodies. One individual had 3 features,
1% or more /+-DNT cells, circulating autoantibodies,
and the presence of autoimmunity. In this group, there was no
relationship between alterations in lymphocyte subsets (other than the
/+-DNT cell subset) and the number and nature of
ALPS features.
Genotype-immunophenotype analysis As has been reported, the location of the mutation within the TNFRSF6 gene has an influence on the penetrance of the ALPS phenotype.18,21 To determine if a similar relationship exists between genotype and the immunophenotypic characteristics, the individuals in the M+/A group were assigned to a subgroup of extracellular TNFRSF6 mutations (exons 1-6, n = 15) or a
subgroup of intracellular mutations in TNFRSF6 (exons 7-9, n = 27). This revealed that there were no associations
between the localization of the mutation and the absolute number of any
of the lymphocyte subsets (data not shown). Likewise, in the proband Ia
group, probands with intracellular mutations (n = 20) had similar
immunophenotypic results as probands with extracellular mutations
(n = 11) (data not shown). Similar ranking was not performed in the
M+/A+ group because all but one in this group belonged to families with
intracellular TNFRSF6 mutations, confirming the reported
increased disease penetrance associated with the intracellular
genotypes.18
In vitro Fas-mediated apoptosis in ALPS patients versus relatives To determine if some of the immunophenotypic and clinical differences between M+/A+ patients and their relatives may stem from differences in the apoptotic defects, EBV-transformed cell lines from a subgroup of 6 ALPS type Ia families, with family members belonging to all of the defined population groups, were analyzed for quantitative defects in Fas-mediated apoptosis. As expected, cells from probands (data not shown) and M+/A+ individuals all had significant apoptotic defects, with intracellular mutations leading to more pronounced defects (Figure 3A) than extracellular mutations (Figure 3B). However, analysis of M+/A relatives from both
groups showed that their apoptotic defects were not significantly different than cells from the M+/A+ family members and probands (data
not shown). M/A family members were not significantly different
than normal controls. Flow cytometric analysis of surface Fas levels
from patients versus controls did also not yield any significant
differences between the M+/A+ and M+/A individuals within a family
(data not shown). Thus, the immunophenotypic differences found between
ALPS patients and mutation-positive relatives without clinical ALPS is
not due to any genetic or epigenetic influence on the apoptosis defect
itself, but more likely stems from other genetic or
environmental factors.
From an immunophenotypic standpoint, ALPS is characterized by expansion of CD3+ T cells, CD8+ T cells, CD3+/HLA-DR+ T cells, CD8+/CD57+ T cells, both DNT cell subsets, total B cells, and CD5+ B cells, as well as low numbers of CD3+/CD25+ T cells, due to a reduction in CD4+/CD25+ T cells. Immunophenotypic profiles of persons in families with ALPS are distinctive for each family group. When the groups are ranked, based on median numbers of cells positive for specific lymphocyte markers, the proband Ia group and the M+/A+ group are clearly distinguishable from the other groups. Although no age-matched controls were used for the proband Ia group,
several findings validate the age-independent significance of the
results. First, comparing younger probands with older probands, as well
as Spearman rank correlation analysis, established the lack of
age-related influences, with the exception of the number of
In an initial survey (data not shown), subjects older than 14 years
from the proband Ia and M+/A+ groups were combined in one group and the
results were comparable to the current results from the M+/A+ group.
This is a further indication that any age-related influence in the
proband Ia group does not have an impact on the overall significance of
the immunophenotypic findings and profiles in ALPS patients, compared
to the profiles of the HC group, M+/A The expansion of HLA-DR+ T cells and CD57+ T
cells in the groups with clinical disease was not observed in the
M+/A The M An increase in CD5+ B cells were significantly increased in the proband Ia
group, the proband II/III group, the M+/A+ group, and the M The CD5+ B-cell expansion in the proband Ia and M+/A+
groups may be related to the elevated levels of circulating
IL-10.19 In support of this hypothesis, there was a
significant correlation between the number of CD5+ B cells
and the level of IL-10 in individuals in the proband Ia group
(rho = .6; P = .02, data not shown). In mice, IL-10 is an essential growth factor for CD5+ B-1 cells, and a factor
capable of preventing apoptosis of B cells, including CD5+
B cells.29-31 The normal levels of IL-10 found in the
M Not all immunophenotypic features of ALPS reflect lymphoaccumulation. The profile of the proband Ia group reveals an absolute decrease in CD25+ T cells, a finding also present in the proband II/III group, but not in the other ALPS Ia family groups. In combination with the increased HLA-DR expression on T cells, these changes are reflected in abnormal CD3+/CD25+-to-CD3+/HLA-DR+ ratios for the proband Ia group, M+/A+ group, and proband II/III group. This measurement is reflective of 2 independent changes, specific for clinical ALPS, regardless of the type, and thus may serve as an immunophenotypic marker of ALPS. The ratio demonstrated a sensitivity and specificity of 83% and 90%, respectively, when using a ratio of 1 or less to discriminate for clinical ALPS, and 95% and 71%, respectively, at a ratio of 1.4 or less (the median ratio of the 166 subjects in the 4 family groups). At these ratios, the specificity of the marker for the HC group was 98% and 88%, respectively. Additional data in subjects of the proband Ia and M+/A+ groups revealed that the reduction in CD25+ T cells was due to a loss of CD4+/CD25+ T cells (Figure 2B). In this regard, it is of interest that the CD4+ T-cell subset is the only T-cell subset not significantly expanded in any of the groups. The loss of CD4+/CD25+ T cells is not the result of accumulation of CD25+ T cells within the DNT pool because CD25+ T cells were accounted for by the CD4+ and CD8+ T-cell subsets. It is also unlikely to be secondary to a redistribution to lymphoid tissue because there is also a paucity of CD25+ T cells in lymph nodes and spleen.12 The in vitro apoptosis data in several ALPS families demonstrate that relatives with TNFRSF6 mutations have comparable levels of defective Fas-mediated apoptosis, regardless of alterations in CD4+/CD25+ T cells, and suggest a contribution of reduced CD4+/CD25+ T cells to the ALPS pathogenesis, through a mechanism independent of the Fas pathway of cellular suicide. A growing body of evidence indicates the importance of CD25 in the life
and death of lymphocytes. CD25-deficient mice develop significant
polyclonal lymphoproliferation and autoimmunity, including autoimmune
hemolytic anemia, which may have both Fas-independent and Fas-dependent
causes.32,33 A naturally occurring defect in human CD25
caused lymphadenopathy and hepatosplenomegaly as well as severe
immunodeficiency.34 Corroboration of the importance of
CD25 has been provided by recent studies in mice, in which CD25+ CD4+ T cells were implicated as
immunoregulatory cells, capable of maintaining self-tolerance and
preventing autoimmunity by suppressing CD25 This comprehensive immunophenotypic study of a human disorder of
defective lymphocyte apoptosis has provided several new insights. Changes in lymphocyte subset distribution in relatives without TNFRSF6 mutations offer support for the concept of
additional contributing factors to the complex pathogenesis of ALPS.
The changes in particular (immunoregulatory) subsets, and the fact that
the apoptotic defects are not more severe in probands and M+/A+
patients than M+/A
CD4+/CD25+ (immunoregulatory) T cells have recently been identified in humans.43-45
Submitted September 19, 2000; accepted June 1, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jack J. H. Bleesing, Arkansas Children's Hospital Research Institute, 1120 Marshall St, Little Rock, AR 72202; e-mail: bleesingjacobh{at}uams.edu.
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Current members of the National Institutes of Health ALPS group are Stephen E. Straus, Jennifer M. Puck, Michael J. Lenardo, Jack J. H. Bleesing, Margaret R. Brown, Hyung Chun, Janet K. Dale, Joie Davis, Faith Dugan, Roxanne E. Fisher, Thomas A. Fleisher, Fred Gill, Amy P. Hsu, John Hurley, Christine E. Jackson, Elaine S. Jaffe, Frances Ka-Ming, Lilia Lei Bi, Adrian Lobito, Julie Niemela, Richard M. Siegel, Michael C. Sneller, Warren Strober, David Stroncek, Jin Wang, and Lixin Zheng.
© 2001 by The American Society of Hematology.
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  J. B. Oliveira, N. Bidere, J. E. Niemela, L. Zheng, K. Sakai, C. P. Nix, R. L. Danner, J. Barb, P. J. Munson, J. M. Puck, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome PNAS, May 22, 2007; 104(21): 8953 - 8958. [Abstract] [Full Text] [PDF]
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 T. Alvaro, M. Lejeune, M.-T. Salvado, C. Lopez, P. Escriva, J. Jaen, R. Bosch, and L. E. Pons In Reply J. Clin. Oncol., April 1, 2007; 25(10): 1291 - 1292. [Full Text] [PDF]
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 C. Xie, R. Patel, T. Wu, J. Zhu, T. Henry, M. Bhaskarabhatla, R. Samudrala, K. Tus, Y. Gong, H. Zhou, et al. PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr Int. Immunol., April 1, 2007; 19(4): 509 - 522. [Abstract] [Full Text] [PDF]
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D. T. Teachey, C. S. Manno, K. M. Axsom, T. Andrews, J. K. Choi, B. H. Greenbaum, J. M. McMann, K. E. Sullivan, S. F. Travis, and S. A. Grupp Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS) Blood, March 15, 2005; 105(6): 2443 - 2448. [Abstract] [Full Text] [PDF]
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 R. Clementi, L. Dagna, U. Dianzani, L. Dupre, I. Dianzani, M. Ponzoni, A. Cometa, A. Chiocchetti, M. G. Sabbadini, C. Rugarli, et al. Inherited Perforin and Fas Mutations in a Patient with Autoimmune Lymphoproliferative Syndrome and Lymphoma N. Engl. J. Med., September 30, 2004; 351(14): 1419 - 1424. [Abstract] [Full Text] [PDF]
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 G. Strauss, I. Knape, I. Melzner, and K.-M. Debatin Constitutive Caspase Activation and Impaired Death-Inducing Signaling Complex Formation in CD95-Resistant, Long-Term Activated, Antigen-Specific T Cells J. Immunol., August 1, 2003; 171(3): 1172 - 1182. [Abstract] [Full Text] [PDF]
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 X. Shi, C. Xie, D. Kreska, J. A. Richardson, and C. Mohan Genetic Dissection of SLE: SLE1 and FAS Impact Alternate Pathways Leading to Lymphoproliferative Autoimmunity J. Exp. Med., August 5, 2002; 196(3): 281 - 292. [Abstract] [Full Text] [PDF]
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M. A. Haque, T. Mizobuchi, K. Yasufuku, T. Fujisawa, R. R. Brutkiewicz, Y. Zheng, K. Woods, G. N. Smith, O. W. Cummings, K. M. Heidler, et al. Evidence for Immune Responses to a Self-Antigen in Lung Transplantation: Role of Type V Collagen-Specific T Cells in the Pathogenesis of Lung Allograft Rejection J. Immunol., August 1, 2002; 169(3): 1542 - 1549. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
CD8
immune regulation in a dynamic and unpredictable antigenic environment.
Annu Rev Immunol.
1999;17:221-252