Subject(s)
Bronchiolitis Obliterans , Hematopoietic Stem Cell Transplantation , Hypertension, Pulmonary , Adolescent , Allografts , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/physiopathology , Child , Female , Humans , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Infant , Male , Retrospective StudiesABSTRACT
MHC Class II deficiency is a rare primary immunodeficiency disease characterized by absent HLA Class II expression resulting in CD4 lymphopenia, lack of Ag-specific responses and recurrent infection. Without successful allogeneic SCT, most children succumb to infection within the first decade of life. To date, alternative donor transplants for this disorder have been inferior to SCT for other forms of combined immunodeficiency disease due to an increased incidence of graft rejection, GVHD and death from infections generally acquired before haematopoietic cell transplantation. This study details the transplant outcome of 16 affected children consecutively transplanted at four centers since 1990, 8 of whom required mechanical ventilation pretransplant. Stem cells were derived from an HLA-mismatched family member (n=10), an HLA-matched unrelated adult donor (n=4), or an unrelated cord blood donor (n=2). Graft failure occurred in five children, all of whom underwent a second SCT. Six patients developed acute GVHD although no patient developed chronic GVHD after primary transplantation. CD4 T-cell reconstitution remained below the normal range for age, suggesting defective thymopoiesis after allo-SCT. Nonetheless, 69% of children survive without GVHD at a median follow-up of 5.7 years, indicating improved outcomes compared with previous studies.
Subject(s)
HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation/methods , Histocompatibility Antigens Class II/immunology , Immunologic Deficiency Syndromes/surgery , Child, Preschool , Female , Histocompatibility Antigens Class II/genetics , Histocompatibility Testing , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Infant , Infant, Newborn , Male , Tissue DonorsABSTRACT
HLA-identical sibling donor transplantation remains the treatment of choice for Wiskott-Aldrich Syndrome (WAS). Since 1990, utilization of alternative donor sources has increased significantly. We report the hematopoietic cell transplantation (HCT) outcomes of 47 patients with WAS treated at a single center since 1990. Improved outcomes were observed after 2000 despite the increased number of alternative donors. Five-year OS improved from 62.5% (95% CI: 34.9% to 81.1%) to 90.8% (95% CI: 67.7% to 97.6%) for patients transplanted during 1990-2000 and 2001-2009, respectively. In multivariate analysis, transplant era significantly impacted OS (P=0.04), whereas age was only marginally significant (P=0.06, Cox proportional hazard analysis). No TRM occurred within the first 100 days among patients transplanted during 2001-2009 compared with 3/16 during 1990-2000, (P=0.03, Fisher's exact test). The extent of HLA mismatch did not significantly affect the incidence of acute GVHD, chronic GVHD or survival. Post-HCT autoimmune cytopenias were frequently diagnosed after 2001: 17/31 (55%) patients. Their occurrence was not associated with transplant donor type (P=0.53), acute GVHD (P=0.74), chronic GVHD (P=0.12), or post-transplant mixed chimerism (P=0.50).
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Wiskott-Aldrich Syndrome/surgery , Adolescent , Adult , Cohort Studies , Humans , Male , Survival Rate , Transplantation Conditioning/methods , Transplantation, Homologous , Treatment Outcome , Wiskott-Aldrich Syndrome/immunology , Young AdultABSTRACT
Patients undergoing auto-SCT for neuroblastoma present a unique population to study transplant-associated thrombotic microangiopathy (TA-TMA), due to standardized chemotherapy and later exposure to radiation and cis-retinoic acid (cis-RA). We retrospectively analyzed 20 patients after auto-SCT to evaluate early clinical indicators of TA-TMA. A total of 6 patients developing TA-TMA (30% prevalence) were compared with 14 controls. Four of six patients were diagnosed with TA-TMA by 25 days after auto-SCT. Compared with controls, TA-TMA patients had higher average systolic and diastolic blood pressure levels during high-dose chemotherapy and developed hypertension by day 13 after auto-SCT. Proteinuria was a significant marker for TA-TMA, whereas blood and platelet transfusion requirements were not. Serum creatinine did not differ between groups post transplant. However, patients with TA-TMA had a 60% decrease in renal function from baseline by nuclear glomerular filtration rate, compared with a 25% decrease in those without TA-TMA (P=0.001). There was no TA-TMA-related mortality. Significant complications included end-stage renal disease (n=1) and polyserositis (n=3). Patients with TA-TMA were unable to complete cis-RA therapy after auto-SCT. We suggest that careful attention to blood pressure and urinalysis will assist in the early diagnosis of TA-TMA, whereas serum creatinine seems to be an insensitive marker for this condition.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Neuroblastoma/surgery , Thrombotic Microangiopathies/diagnosis , Antihypertensive Agents/therapeutic use , Blood Pressure , Case-Control Studies , Child, Preschool , Female , Humans , Hypertension/drug therapy , Hypertension/etiology , Male , Proteinuria/etiology , Retrospective Studies , Thrombotic Microangiopathies/complications , Thrombotic Microangiopathies/etiology , Transplantation Conditioning , Transplantation, AutologousABSTRACT
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman-Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III-IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.
Subject(s)
Abnormalities, Multiple/surgery , Pancreatic Diseases/surgery , Stem Cell Transplantation , Transplantation Conditioning/methods , Adult , Alemtuzumab , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm/therapeutic use , Child , Child, Preschool , Drug Therapy, Combination , Female , Graft vs Host Disease/prevention & control , Humans , Male , Melphalan/therapeutic use , Transplantation Conditioning/adverse effects , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
Allogeneic hematopoietic cell transplantation (HCT) in patients with Hurler's syndrome can improve survival and ameliorate many aspects of Hurler's syndrome including neurologic decline and cardiac compromise. Unfortunately, the toxicity of traditional preparative regimens to organs affected by the syndrome may have deleterious effects. Additionally, despite the intensity of these regimens, achieving stable donor chimerism can be difficult. We report transplant outcomes following a reduced intensity, highly immunosuppressive preparative regimen consisting of alemtuzumab, fludarabine and melphalan prior to HCT in seven patients with Hurler's syndrome treated at two centers. Six patients received grafts from unrelated donors and one received a sibling donor graft. The preparative regimen was well tolerated. All patients had initial donor engraftment at 100 days; one patient had delayed loss of donor chimerism. There was no severe acute GVHD (no GI GVHD of grade II or more, no grade IV skin GVHD). Six of the seven children are surviving at a median of 1014 (726-2222) days post transplant. This reduced intensity preparative regimen has the potential to support engraftment and improve survival and outcome in patients with Hurler's syndrome undergoing HCT.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunosuppressive Agents/therapeutic use , Mucopolysaccharidosis I/therapy , Transplantation Conditioning/methods , Adolescent , Adult , Alemtuzumab , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm/therapeutic use , Child , Female , Graft Survival , Humans , Male , Melphalan/therapeutic use , Pilot Projects , Survival Analysis , Transplantation, Homologous , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useSubject(s)
Amino Acid Substitution/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Membrane Glycoproteins/genetics , Mutation, Missense , Pore Forming Cytotoxic Proteins/genetics , Alanine/genetics , Family Health , Genetic Carrier Screening , Genotype , Humans , Lymphohistiocytosis, Hemophagocytic/immunology , Perforin , Valine/geneticsABSTRACT
Activated T cells undergo changes during their transition to T cell blasts and, subsequently, via a phase of anergy, to apoptosis. For example, activated murine T cell blasts express the B-cell-specific CD45R isoform, B220, a marker also present on T cells in mice and humans with defective Fas-mediated apoptosis in vivo, suggesting a role for B220 up-regulation in the transition of activation to apoptosis. Human T cells, activated in vitro with superantigens and mitogens, also express B220 as they undergo blastogenesis and cell cycle progression. B220 expression peaks on T cells undergoing apoptosis. CD43-hexasaccharide glycoform expression and lectin binding profiles indicate that B220 expression is reflective of altered O-linked glycan biosynthesis found in specific T cell subsets transitioning through the phases of proliferation, anergy, and apoptosis. Potential implications of these alterations include changes in lymphocyte adhesion and trafficking and homeostasis through altered sensitivity to Fas-dependent and independent pathways of apoptosis.
Subject(s)
Apoptosis , Leukocyte Common Antigens/biosynthesis , Polysaccharides/biosynthesis , T-Lymphocytes/metabolism , Adult , Animals , Annexin A5 , Antibodies, Monoclonal/immunology , Antibody Specificity , Cell Membrane/metabolism , Cells, Cultured , Enterotoxins/pharmacology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation , Mice , Mitogens/pharmacology , Phytohemagglutinins/pharmacology , Protein Isoforms/biosynthesis , Staining and Labeling/methods , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Up-Regulation/drug effectsABSTRACT
The effect of mixed chimerism on the pace of post-transplant immune reconstitution is unknown. Using flow cytometry, recall and neo-antigen vaccine responses, and T cell receptor recombination excision circle (TREC) quantification, we evaluated phenotypic and functional characteristics of T and B cells in nine patients following non-myeloablative, HLA-identical peripheral blood stem cell transplantation for chronic granulomatous disease. Engraftment of T cell, B cell, and myeloid lineages proceeded at similar paces within each patient, but engraftment kinetics segregated patients into two groups: adults, who became full donor T cell chimeras before 6 months (rapid engrafters) and children, who became full donor T cell chimeras after 6 months or not at all (slow engrafters). Quantitative B cell recovery was achieved by 6 weeks after transplantation in children, but was delayed until 1 year in adults. Early quantitative B cell recovery was not accompanied by an early humoral immune response to tetanus toxoid (TT). Emergence of TT-specific T cell responses coincided with naive T cell reconstitution, as measured by CD4/CD45RA T cell recovery and TREC quantification. These data suggest that immune reconstitution occurs faster in pediatric patients who have prolonged mixed hematopoietic chimerism compared to adults, who have rapid donor stem cell engraftment.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphocyte Subsets/immunology , Myeloablative Agonists/therapeutic use , Transplantation Chimera/immunology , Transplantation Conditioning/methods , Adolescent , Adult , Age Factors , Child , Child, Preschool , Female , Gene Rearrangement, T-Lymphocyte , Granulomatous Disease, Chronic/immunology , Granulomatous Disease, Chronic/therapy , Humans , Immunoglobulins/blood , Lymphocyte Count , Male , Tissue DonorsABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) type Ia is caused by inherited defects in apoptosis and is characterized by nonmalignant lymphoaccumulation, autoimmunity, and increased alpha/beta(+) double-negative T cells (alpha/beta(+)-DNT cells). This study reports immunophenotypic findings in 166 members of 31 families with ALPS type Ia, associated with genetic mutations in the TNFRSF6 gene encoding Fas. The ALPS type Ia probands (n = 31) and relatives having both a Fas mutation and clinically proven ALPS (n = 28) showed significant expansion of CD8(+) T cells, alpha/beta(+)-DNT cells, gamma/delta(+)-DNT cells, CD3(+)/ HLA-DR(+) T cells, CD8(+)/CD57(+) T cells, and CD5(+) B cells. Relatives with Fas mutations, but without all the required criteria for ALPS (n = 42), had expansions of CD8(+) T cells, alpha/beta(+)-DNT cells, and gamma/delta(+)-DNT cells. Interestingly, relatives without a Fas mutation and with no features of ALPS (n = 65) demonstrated a small but significant expansion of CD8(+) T cells, both DNT cell subsets, and CD5(+) B cells. As compared to unrelated healthy controls, lymphocyte subset alterations were greatest in the probands, followed by the relatives with mutations and ALPS. Probands and relatives with mutations and ALPS also showed a lower number of CD4(+)/CD25(+) T cells that, in combination with an independent increase in HLA-DR(+) T cells, provided a profile predictive of the presence of clinical ALPS. Because quantitative defects in apoptosis were similar in mutation-positive relatives regardless of the presence of clinical ALPS, factors, other than modifiers of the Fas apoptosis pathway, leading to these distinctive immunophenotypic profiles most likely contribute to disease penetrance in ALPS.
Subject(s)
Autoimmune Diseases/immunology , Lymphocyte Subsets/immunology , Lymphoproliferative Disorders/immunology , Adult , Aged , Aged, 80 and over , Antigens, CD/blood , Antigens, CD/genetics , Antigens, CD/immunology , Apoptosis , Autoimmune Diseases/genetics , Female , Flow Cytometry , HLA-DR Antigens/genetics , Humans , Immunophenotyping/methods , Lymphoproliferative Disorders/blood , Lymphoproliferative Disorders/genetics , Male , Middle Aged , Racial Groups , Receptors, Antigen, T-Cell, alpha-beta/genetics , Syndrome , T-Lymphocytes/immunology , United States , fas Receptor/geneticsABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS), caused by inherited defects in apoptosis secondary to mutations in genes encoding Fas/CD95/APO-1 and Fas ligand (Fasl)/CD95L, is characterized by nonmalignant lymphadenopathy and splenomegaly, increased T cell receptor alpha/beta(+) CD4(-)CD8(-) T cells (alpha/beta(+) double-negative T cells [alpha/beta(+)-DNT cells]), autoimmunity, hypergammaglobulinemia, and cytokine abnormalities. The alpha/beta(+)-DNT cells are immunophenotypically and functionally similar to alpha/beta(+)-DNT cells that accumulate in lpr and gld mice, which bear genetic mutations in Fas and FasL. In these mice, alpha/beta(+)-DNT cells express the B-cell-specific CD45R isoform B220. We show that alpha/beta(+)-DNT cells of ALPS patients, with either Fas or FasL mutations, also express B220. In addition, also similar to LPR/gLD mice, they have an unusual population of B220-positive CD4(+) T cells. B220 expression, together with our finding of characteristic lectin binding profiles, demonstrates that cell surface O-linked glycoproteins have undergone specific modifications, which may have consequences for lymphocyte trafficking, cell-cell interactions, and access to alternative apoptosis pathways.
Subject(s)
Autoimmune Diseases/immunology , CD4 Antigens/analysis , CD8 Antigens/analysis , Leukocyte Common Antigens/analysis , Lymphoproliferative Disorders/immunology , Polysaccharides/biosynthesis , Receptors, Antigen, T-Cell, alpha-beta/analysis , T-Lymphocytes/chemistry , Biomarkers , Humans , Membrane Glycoproteins/analysis , Protein IsoformsABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P <.001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA; P <.001 and P <.01, respectively). By fractionating PBMC populations, disproportionately high concentrations of IL-10 mRNA were found in the CD4(-)CD8(-) T-cell population, expansion of which is virtually pathognomonic for ALPS. Immunohistochemical staining showed intense IL-10 protein signals in lymph node regions known to contain CD4(-)CD8(-) T cells. Nonetheless, in vitro studies showed no influence of IL-10 on the survival of CD4(-)CD8(-) T cells. Overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS.
Subject(s)
Autoimmune Diseases/metabolism , Interleukin-10/metabolism , Lymphoid Tissue/metabolism , Lymphoproliferative Disorders/immunology , Apoptosis , Autoimmune Diseases/blood , Autoimmune Diseases/genetics , CD4 Antigens/analysis , CD8 Antigens/analysis , Cell Survival , Child , Child, Preschool , Female , Humans , Infant , Interleukin-10/blood , Interleukin-10/genetics , Leukocytes, Mononuclear/chemistry , Lymphoproliferative Disorders/blood , Lymphoproliferative Disorders/genetics , Male , RNA, Messenger/blood , T-Lymphocytes/immunology , T-Lymphocytes/physiologyABSTRACT
Immunophenotyping of leukocytes for nonmalignant conditions uses the power of multiparameter flow cytometry to count specific lymphocyte populations and evaluate the presence or absence of particular cell surface markers. Its main clinical indications, and the focus of this chapter, are enumeration of CD4 T-cell counts and activation markers on T cells in human immunodeficiency virus (HIV) infection, immunophenotypic characterization of primary immunodeficiency disorders and immune-mediated diseases, and the study of immune reconstitution following stem cell transplantation (SCT). Immunophenotyping has advanced our understanding of many immunologic disorders, which in turn have stimulated new developments in the field of flow cytometry, such as quantitative flow cytometry and single-platform technology. Semin Hematol 38:100-110. This is a US government work. There are no restrictions on its use.
Subject(s)
Immunophenotyping/instrumentation , Animals , Flow Cytometry , Humans , Immune System/immunology , Immune System/pathology , Immune System/virology , Immunophenotyping/methods , Lymphocytes/immunology , Lymphocytes/pathology , Stem Cells/cytology , Stem Cells/immunologyABSTRACT
Flow cytometry is increasingly used to assess the functional status of leukocytes, and practically all aspects of their life (and death) are accessible to flow cytometric study. Together with familiar features of flow cytometry, such as multiparameter immunophenotyping, cell function-based flow cytometry has provided many new insights into the relationships among lymphocyte cell surface features; intracellular processes, such as cytokine production and protein phosphorylation; and the functional status of lymphocytes in a variety of human diseases. Direct visualization and quantification of antigen-specific T cells using major histocompatibility complex (MHC)-peptide tetramer technology, in combination with functional assays, has provided the means to study specific T-cell subsets of interest. Even early in its development, this technology already has offered a better understanding of basic and clinical immunology and has invited reassessment of several long-standing immunologic concepts. Semin Hematol 38:169-178. This is a US government work. There are no restrictions on its use.
Subject(s)
Flow Cytometry/methods , Leukocytes/cytology , Animals , Cytokines/analysis , Humans , Leukocytes/immunology , Leukocytes/physiology , Major Histocompatibility Complex/physiology , Phagocytes/metabolism , Phosphorylation , Respiratory BurstABSTRACT
Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.
Subject(s)
Protein-Tyrosine Kinases/deficiency , Adolescent , Amino Acid Sequence , B-Lymphocytes/metabolism , Cell Line, Transformed , Child , DNA, Complementary , Fas Ligand Protein , Female , Gene Expression , Humans , Immunophenotyping , Interleukin-2/metabolism , Janus Kinase 3 , Male , Membrane Glycoproteins/metabolism , Molecular Sequence Data , Mutation , Pedigree , Protein-Tyrosine Kinases/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Interleukin-2/metabolism , Sequence Analysis, DNA , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/pathology , Signal Transduction , T-Lymphocytes , Up-RegulationABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) is a recently characterized human disorder that typically presents with lymphocyte accumulation in the first few years of life. This is often associated with the development of autoimmunity, most commonly affecting the hematopoietic system. A key laboratory feature is the marked expansion of double-negative (CD4- and CD8-) T cells that express the alpha/beta T-cell receptor. ALPS is associated with defective Fas-mediated lymphocyte apoptosis, and in most patients, this results from a heterozygous mutation in the TNFRSF6 gene encoding Fas. The clinical features of ALPS reveal the importance of the Fas apoptotic pathway in maintaining lymphocyte homeostasis and protecting against autoimmunity and lymphoid malignancy.
Subject(s)
Apoptosis/immunology , Autoimmune Diseases/genetics , Lymphoproliferative Disorders/genetics , fas Receptor/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , CD4 Antigens , CD8 Antigens , Heterozygote , Homeostasis/immunology , Humans , Lymphoproliferative Disorders/immunology , Lymphoproliferative Disorders/pathology , Mutation , Receptors, Antigen, T-Cell, alpha-beta , T-Lymphocytes/immunology , fas Receptor/physiologyABSTRACT
The innate and the adaptive immune systems have evolved to provide a rapid and specific means for protecting hosts against the many microbes experienced over a lifetime. These two immune responses interact cooperatively to enhance the host defense. Defects in either of these two pathways can have devastating consequences, as evidenced [figure: see text] by primary immune deficiencies, many of which are discussed in this issue of the Pediatric Clinics of North America. The immune system has a central role in the pathogenesis of many disorders that involve an inflammatory response, including allergic and autoimmune diseases. New and more effective therapies for these many disorders will develop as the understanding of the immune system and its many secreted mediators continues to increase.
Subject(s)
Immunity, Active/physiology , Immunity, Cellular/physiology , B-Lymphocytes/immunology , Child , Child, Preschool , Female , Humans , Immune System/physiology , Immunity, Innate/physiology , Infant , Male , Sensitivity and Specificity , T-Lymphocytes/immunologyABSTRACT
The importance of Fas in the homeostatic balance between lymphocyte survival and death is underscored by the three main consequences of defective Fas-mediated apoptosis, as experienced by patients with ALPS: (1) abnormal accumulation of lymphocytes results in lymphadenopathy, hepatosplenomegaly, and hypersplenism; (2) failure of removal of potentially autoreactive lymphocytes, a process normally used to eliminate lymphocytes that have escaped negative selection in the thymus and bone marrow (see article by Fleisher and Blessing, p. 1197), is associated with the appearance of autoimmune manifestations; and (3) inappropriate survival of lymphocytes may lead to the development of malignancies. As with other "experiments of nature," the many aspects of ALPS have provided valuable new insights into the immune system and the importance of a proper balance between life and death of lymphocytes. ALPS is an example of how a mouse disease model was applied directly to the identification of the molecular basis and the understanding of a remarkable disease in humans. It is also an example of clinical observations being linked to basic scientific data to unlock the underlying defect(s) causing a disease. Despite the difficulty in fully understanding the complex nature of the clinical course, the immunologic abnormalities, and the genetic aspects of ALPS, the accumulated experience in diagnosis, treatment, and follow-up of patients and relatives has generated a "road map" that can be used as a guide for their care. As examples, the appreciation that manifestations of lymphoproliferation usually subside over time has allowed a "wait-and-see" approach in many patients who might previously have been treated aggressively. The appreciation that these patients are at increased risk for malignancies has mandated the adoption of careful and lifelong follow-up. Future efforts directed at careful clinical follow-up and scientific investigation are required to learn more about the incidence and natural history of ALPS, therapeutic interventions directed at altering the consequences of TNFRSF6 mutations, and the identification of other genetic and environmental factors that may have a role in the pathogenesis of ALPS.