Background
Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of lymphocyte homeostasis. It is defined as a chronic (>6 months) non-malignancy and non-infectious uncontrolled proliferation of lymphocytes commonly accompanied by autoimmune manifestations, lymphadenopathy, splenomegaly, and susceptibility to malignancies. [1] ALPS is the first disease known to be caused by a primary defect in programmed cell death and the first description of a monogenic cause of autoimmune disease. The first genetic defect was described in 1995 by the discovery of the FAS gene mutation. [2] Other ALPS-associated genetic defects in the apoptotic pathway and ALPS-like disorders (ALPS-related syndromes) have subsequently been identified.
An illustrative case of ALPS is as follows:
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A 10-year-old male presented with a history of lymphadenopathy, splenomegaly, and onset of multilineage cytopenias as an infant, with subsequent splenectomy at age 13 months
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After undergoing the splenectomy, the patient developed pneumococcal meningitis, which led to hearing loss that required a cochlear implant
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Subsequently, the patient experienced several episodes of pneumococcal sepsis, chronic osteomyelitis, profound neutropenia, vasculitis, autoimmune hemolytic anemia, and thrombocytopenia, with many hospitalizations and intensive care unit (ICU) admissions for treatment of these complications
This patient’s repeated infections with encapsulated organisms highlight the importance of maintaining the spleen in ALPS patients, if possible. The constellation of lymphadenopathy, splenomegaly, and autoimmune cytopenias necessitating long-term immunosuppressive treatment with mycophenolate mofetil makes diagnosis and management of these patients quite challenging.
Pathophysiology
Apoptosis is a genetically regulated form of nonimmunogenic cell death. Its roles in biologic processes, including embryogenesis, aging, and many diseases, are crucial. It may be activated via death receptors (extrinsic pathway) or mitochondrial (intrinsic pathway). A failure of apoptosis leads to inappropriate cell survival and diseases associated with excessive accumulations of cells such as cancer, chronic inflammatory conditions, and autoimmune diseases. [3]
Apoptosis is most often mediated by extrinsic pathway via FAS or CD95 or apoptosis antigen 1 (APO-1) or tumor necrosis factor receptor superfamily 6 (TNFRSF6), a cell surface death receptor. Under physiologic conditions, lymphocyte activation is followed by apoptosis when FAS ligand (FASL) interacts with FAS; this results in cytoplasmic recruitment of a protein known as the FAS-associated death domain (FADD), followed by recruitment of procaspase 8 and procaspase 10 and resultant cellular apoptosis.
The essential role of FAS plays in maintaining lymphocyte homeostasis and peripheral immune tolerance to prevent autoimmunity was first demonstrated by studying FAS-deficient MRL/lpr-/- mice. Mice homozygous for FAS mutations develop hypergammaglobulinemia, glomerulonephritis, massive lymphadenopathy, and expansion of an otherwise rare population of T-cell receptor (TCR) α/β cells that lack expression of both CD4 and CD8 (double-negative T [DNT] cells). [4] This provided insights into the pathophysiology of a similar syndrome seen in humans. [5]
ALPS, as this disorder was subsequently named in humans [2] , is caused by a failure of apoptotic mechanisms to maintain lymphocyte homeostasis leading to abnormal lymphocyte survival. Most cases of ALPS are caused by loss-of-function mutations in components of the FAS apoptotic pathway or extrinsic pathway. The most common genetically defined ALPS is the autosomal dominant transmission of heterozygous germline mutations in FAS (70%), and the second common is somatic FAS mutations (10–15%). Other autosomal recessive transmissions in FAS-mediated apoptotic pathway causing ALPS are genes encoding CASP10 (< 1%) and FASL (< 1%). [6] Some patients may have a compound heterozygous mutation or more than one mutation, such as FAS mutation and CASP10 mutation. [7] Approximately 20% of ALPS does not have an identifiable mutation.
ALPS is rarely caused by a defect of mitochondrial apoptosis or intrinsic pathway. A heterozygous germline gain of function mutation encoding NRAS, an oncogene, leading to a failure of apoptosis in response to interleukin-2 withdrawal was identified as the first intrinsic pathway defect causing ALPS. [8]
The extrinsic pathway of apoptosis. Mutations have been identified in each of the genes coding for Fas, Fas-ligand (FasL), caspase-8, and caspase-10. This figure was previously published in Rao VK, Straus SE. Autoimmune Lymphoproliferative Syndrome. Clinical Hematology. 58;759. 2006: Elsevier.
The defective apoptosis results in lymphoproliferation with appropriate persistence and accumulation of autoreactive or potentially oncogenic lymphocytes, leading to splenomegaly and lymphadenopathy with an increased risk of Hodgkin and non-Hodgkin lymphoma.
The lymphoproliferation is mainly characterized by the accumulation of CD3+TCRα/β + CD4-CD8- or DNT cells in the peripheral blood (>2.5% of T cells) and lymphoid tissues. These DNT cells likely derive from CD8+ T cells since the DNT cells from ALPS patients share a CDR3 sequence with CD8+ T cell across several TCRVβ families. [9] The DNT cells in ALPS are unique since they do proliferate, produce high IL-10, and display other surface markers including, B220, CD27, CD28, CD57, and CD45RA. The significance of these DNT cells in ALPS is not fully understood. However, the number of DNT cells correlates with the presence of autoantibodies in ALPS. [10]
The number of DNT cells in normal individuals are less than 2% of T cells. Mildly elevated DNT cells can be detected in other autoimmune/ inflammatory conditions [11] and hemophagocytic syndromes. [12] The positive CD57, CD45RA markers can distinguish between DNT cells from ALPS and DNT cells from other conditions. [1]
It is unknown whether B cell development is normal in ALPS. Normal B cell numbers with elevated IgG, IgA are common. [13] Abnormal B cell functions related to disorganized splenic marginal zone but not an intrinsic B cell defect are reported including low serum IgM, low blood memory B cells and poor anti-polysaccharide antibody production with a higher risk of pneumococcal septicemia. [14]
Other immune cells, including gdT cells, NK-T cells, and NK cells, are not affected by ALPS.
Investigation of family members of ALPS patients has revealed a population with identical genetic mutations and same apoptosis defects but can be asymptomatic without elevated DNT cells, IL-10 or soluble FASLG. Additionally, some of the healthy mutation-positive controls had biomarker evidence of disease but are asymptomatic, whereas other family members had very mild disease. These findings suggest that FAS mutations causing cellular apoptosis abnormalities alone are not sufficient to cause clinical APS; and the pathophysiology of ALPS is multifactorial, with an autosomal dominant inheritance pattern and variable penetrance. [15, 16]
Autoimmune lymphoproliferative syndrome (ALPS) classification and ALPS-related syndrome (ALPS-like disorder)
The nomenclature for the various types of ALPS is determined based on the genetic mutation present in an individual. Patients meeting diagnostic criteria for ALPS in whom no genetic mutation can be identified and classified as ALPS–undetermined.
ALPS-like disorders or ALPS-related syndromes are diseases which have similar features of those with ALPS but are missing required diagnostic features such as elevated DNT cells or have additional manifestations such as immunodeficiency features (Table 1). ALPS-like disorders should be considered and evaluated in any patients with clinical features of ALPS.
Table 1. ALPS-like disorders or ALPS-related syndromes [6, 17] (Open Table in a new window)
| Disease | Mutation | Clinical Features |
|---|---|---|
| Caspase-8 deficiency state (CEDS) | Autosomal recessive/ LOF mutation in CASP8 gene (2q33.1) | Recurrent sinopulmonary infections, severe mucocutaneous herpes simplex viral infection with defects in activation of T, B and NK cells, hypogammaglobulinemia, low pneumococcal antibodies, low T cell function (lymphocyte mitogen stimulation), low NK function [18] |
| FADD deficiency | Autosomal recessive/ LOF mutation in FADD gene (11q13.3) | Susceptibility to bacterial and viral infections related to functional hyposplenism and impaired interferon immunity, congenital heart disease, recurrent fever, liver dysfunction, seizures [19] |
| Ras-associated autoimmune leukoproliferative disorder | Germline or somatic mutations/ GOF mutation in NRAS gene (1p13.2) and KRAS gene (12p12.1) | Lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, autoimmunity [20, 21, 22] |
| Dianzani autoimmune lymphoproliferative disease | N252S and A91B perforin gene variations, osteopontin polymorphism | No increased DNT, defective Fas, lymphadenopathy, splenomegaly, autoimmunity [23, 24] |
| Activated phosphoinositide 3-kinase δ syndrome (APDS) | Autosomal dominant/ gain of function mutations in PIK3CD (1p36.22), PIK3R1(5q13.1) | Combined immunodeficiency with recurrent sinopulmonary infections, lymphadenopathy, herpesvirus infection, autoinflammatory disease, lymphoma and neurodevelopmental delay [25] |
| Protein kinase C delta (PRKCD) deficiency | Autosomal recessive/ loss of function mutation in PRKCD gene (3p21.1) | Hypogammaglobinemia, recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity and NK cell dysfunction [26, 27] |
| Lipopolysaccharide responsive and beige like anchor protein (LABA) deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration and enteropathy (LATAIE) | Autosomal recessive/ loss of function mutation in LPS-responsive and beige-like anchor protein (LABA) gene (4q31.3) | Autoimmunity, chronic diarrhea, enteropathy or IBD–like disease, splenomegaly, pneumonia, reduction in number of regulatory T cell, CD4 T cells, class-switched memory B cell and hypogammaglobinemia [28] |
| CTLA4 haloinsufficiency with autoimmune infiltration (CHAI) | Autosomal dominant/ LOF in CTLA4 gene (2q33.2) | Hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, and respiratory, gastrointestinal, or neurological symptoms [29] |
| GOF mutations in STAT1 | Autosomal dominant/ GOF mutation in STAT1 gene (2q32.2) | Recurrent infections including chronic mucocutaneous candidiasis (CMC), recurrent Staphylococcus aureus, recurrent herpes, Mycobacterium, autoimmunity, cytopenia and aneurysm [30] |
| GOF mutations in STAT3 | Autosomal dominant/ GOF mutation in STAT3 gene (17q21.2) |
Hypogammaglobulinemia, autoimmunity, cytopenia, lymphadenopathy, splenomegaly, enteropathy, interstitial lung disease, endocrinopathy, postnatal growth failure [31, 32] |
Deficiency of adenosine deaminase 2 (DADA2) |
Autosomal recessive adenosine deaminase-2 (ADA2) gene (22q11.1) | Recurrent fever, vasculitis, aneurysms, hypertension, ischemic or hemorrhagic stroke, livedo reticularis, lymphadenopathy, hepatosplenomegaly,hypogammaglobulinemia, cytopenia, lymphopenia [33, 34] |
| B cell expansion with NF-B and T cell anergy disease (BENTA) | Autosomal dominant, GOF mutation in CARD11 gene (7p22.2) | Lymphadenopathy, splenomegaly, autoimmunity, cytopenia, low antibodies, recurrent bacterial infections, chronic viral (EBV, molluscum) infections, B cell lymphoma [35, 36] |
Deregulation of Fas ligand expression caused by IL-12RB1 mutation |
Autosomal recess, LOF mutation in IL12RB1 gene (19p13.11) | Lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10 [37] |
| X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) | LOF mutation in MAGT1 gene (Xq21.1) | Persistent Epstein–Barr virus (EBV) viremia, history of EBV+ lymphoma, a CD4:CD8 T-cell ratio of 1 or less with a normal lymphocyte count or mild to moderate lymphopenia, recurrent sinopulmonary and viral infections, hypogammaglobulinemia, variable antibody response to vaccinations, neutropenia, autoimmunity [38, 39] |
Etiology
For most cases of ALPS, the genetic mutation has been identified in the extrinsic apoptosis pathway. The mutation in the intrinsic pathway is extremely rare. [1, 8] Although 20% of ALPS patients have no identifiable mutation that leads to their defective lymphocyte apoptosis, they may still meet the diagnostic criteria for ALPS or an ALPS-related disorder (see Workup).
In patients with ALPS, the disease process can often be explained by the failure to eliminate redundant lymphocyte populations properly. As noted (see above), lymphocytes that are potentially autoreactive or oncogenic predispose these patients to the development of autoimmune diseases and lymphoma.
Epidemiology
The initial presentations of ALPS include persistent lymphadenopathy (>95%) or splenomegaly (>90%) followed by autoimmune cytopenias (>70%) such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), and hepatomegaly (50%) in an otherwise healthy child. [15, 16] To meet the case definition of ALPS, a patient must have chronic, nonmalignant lymphadenopathy or splenomegaly that lasts for 6 months or longer.
Associated multilineage cytopenias due to autoantibodies or splenic sequestration can lead to petechiae, bleeding, pallor, icterus, fatigue, and recurrent infections; the latter are mostly due to neutropenia. A family history of similar disorders may be noted; these are usually inherited in an autosomal dominant fashion. A thorough review of a patient’s extended family for a history of adenopathy, cytopenias, splenectomies, or lymphoma can provide clues in diagnosing ALPS.
Careful attention to the development of systemic B symptoms (eg, fever, drenching night sweats, pruritus, and weight loss) is important for cancer surveillance in those at high-risk for B cell lymphoma. Some of the patients may develop other specific organ autoimmunity or systemic autoimmune diseases such as autoimmune hepatitis, glomerulonephritis, uveitis, and Guillain-Barre syndrome.
Prognosis
The mortality and morbidity of ALPS vary widely. The major determinants of prognosis in patients diagnosed with ALPS include the following:
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The severity of autoimmune disease (particularly autoimmune cytopenias)
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Hypersplenism
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Asplenia-related sepsis
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Development of lymphoma
Addressing these serious conditions with proper surveillance and education is vital for an optimal prognosis. Patients with mutations of the intracellular region of the Fas protein have a significantly increased risk of developing lymphoma and warrant the most diligent long-term surveillance. Despite the numerous potentially serious complications, the overall prognosis for patients with ALPS is good.
Many patients are expected to live a normal lifespan, with few clinical complications. [6] However, a significant number of patients develop childhood-onset life-threatening cytopenias, which necessitate interventions such as hospitalization, immunosuppressive therapy, blood transfusion, antibiotic therapy, or splenectomy. These cytopenias are often chronic and refractory.
As pediatric ALPS patients develop into adolescents and young adults, the degree of adenopathy (particularly visible adenopathy) tends to decrease. The natural course of the adenopathy should be discussed with the patients and their families, particularly during adolescence, when visible adenopathy can be particularly distressing.
Patient Education
As with all chronic diseases, appropriate management of ALPS requires continual reinforcement and education regarding matters of adequate nutrition and control of potential adverse effects of medications. Also, as with many chronic diseases with an onset in childhood, adolescence and early adulthood may provide the additional treatment challenge of poor compliance with prescribed medications. Individual responsibility should be encouraged and emphasized by the treatment team.
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Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.
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Autoimmune lymphoproliferative syndrome (ALPS) and ALPS-related disorders classification:
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Primary and accessory diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS).
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A patient with autoimmune lymphoproliferative syndrome (ALPS) who developed pneumococcal sepsis, a serious complication secondary to neutropenia and asplenia. Note the patient's cochlear implant; he has neurosensory hearing loss from prior episode of pneumococcal meningitis.
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Positron emission tomography (PET) superimposed over a CT scan from a patient with autoimmune lymphoproliferative syndrome (ALPS). Note the massive cervical adenopathy. PET scans may be used as a screening tool in patients with autoimmune lymphoproliferative syndrome to decrease the number of lymph node biopsies used in screening for malignancy.
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The extrinsic pathway of apoptosis. Mutations have been identified in each of the genes coding for Fas, Fas-ligand (FasL), caspase-8, and caspase-10. This figure was previously published in Rao VK, Straus SE. Autoimmune Lymphoproliferative Syndrome. Clinical Hematology. 58;759. 2006: Elsevier.
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Suggested treatment algorithm for patients with autoimmune lymphoproliferative syndrome (ALPS). This schematic diagram is included only as a suggested guideline for managing children with autoimmune lymphoproliferative syndrome–associated autoimmune multilineage cytopenias. Use of granulocyte-colony stimulating factor (G-CSF) may be warranted for severe neutropenia associated with systemic infections. Similarly, use of other chemotherapeutic and immunosuppressive agents (eg, vincristine, methotrexate, mercaptopurine, azathioprine, cyclosporine, hydroxychloroquine, tacrolimus, sirolimus) besides mycophenolate mofetil (MMF) should be considered as a steroid-sparing measure or while avoiding or postponing surgical splenectomy at the discretion of the treating clinicians based on the circumstances of a specific patient.
Tables
| Disease | Mutation | Clinical Features |
|---|---|---|
| Caspase-8 deficiency state (CEDS) | Autosomal recessive/ LOF mutation in CASP8 gene (2q33.1) | Recurrent sinopulmonary infections, severe mucocutaneous herpes simplex viral infection with defects in activation of T, B and NK cells, hypogammaglobulinemia, low pneumococcal antibodies, low T cell function (lymphocyte mitogen stimulation), low NK function [18] |
| FADD deficiency | Autosomal recessive/ LOF mutation in FADD gene (11q13.3) | Susceptibility to bacterial and viral infections related to functional hyposplenism and impaired interferon immunity, congenital heart disease, recurrent fever, liver dysfunction, seizures [19] |
| Ras-associated autoimmune leukoproliferative disorder | Germline or somatic mutations/ GOF mutation in NRAS gene (1p13.2) and KRAS gene (12p12.1) | Lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, autoimmunity [20, 21, 22] |
| Dianzani autoimmune lymphoproliferative disease | N252S and A91B perforin gene variations, osteopontin polymorphism | No increased DNT, defective Fas, lymphadenopathy, splenomegaly, autoimmunity [23, 24] |
| Activated phosphoinositide 3-kinase δ syndrome (APDS) | Autosomal dominant/ gain of function mutations in PIK3CD (1p36.22), PIK3R1(5q13.1) | Combined immunodeficiency with recurrent sinopulmonary infections, lymphadenopathy, herpesvirus infection, autoinflammatory disease, lymphoma and neurodevelopmental delay [25] |
| Protein kinase C delta (PRKCD) deficiency | Autosomal recessive/ loss of function mutation in PRKCD gene (3p21.1) | Hypogammaglobinemia, recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity and NK cell dysfunction [26, 27] |
| Lipopolysaccharide responsive and beige like anchor protein (LABA) deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration and enteropathy (LATAIE) | Autosomal recessive/ loss of function mutation in LPS-responsive and beige-like anchor protein (LABA) gene (4q31.3) | Autoimmunity, chronic diarrhea, enteropathy or IBD–like disease, splenomegaly, pneumonia, reduction in number of regulatory T cell, CD4 T cells, class-switched memory B cell and hypogammaglobinemia [28] |
| CTLA4 haloinsufficiency with autoimmune infiltration (CHAI) | Autosomal dominant/ LOF in CTLA4 gene (2q33.2) | Hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, and respiratory, gastrointestinal, or neurological symptoms [29] |
| GOF mutations in STAT1 | Autosomal dominant/ GOF mutation in STAT1 gene (2q32.2) | Recurrent infections including chronic mucocutaneous candidiasis (CMC), recurrent Staphylococcus aureus, recurrent herpes, Mycobacterium, autoimmunity, cytopenia and aneurysm [30] |
| GOF mutations in STAT3 | Autosomal dominant/ GOF mutation in STAT3 gene (17q21.2) |
Hypogammaglobulinemia, autoimmunity, cytopenia, lymphadenopathy, splenomegaly, enteropathy, interstitial lung disease, endocrinopathy, postnatal growth failure [31, 32] |
Deficiency of adenosine deaminase 2 (DADA2) |
Autosomal recessive adenosine deaminase-2 (ADA2) gene (22q11.1) | Recurrent fever, vasculitis, aneurysms, hypertension, ischemic or hemorrhagic stroke, livedo reticularis, lymphadenopathy, hepatosplenomegaly,hypogammaglobulinemia, cytopenia, lymphopenia [33, 34] |
| B cell expansion with NF-B and T cell anergy disease (BENTA) | Autosomal dominant, GOF mutation in CARD11 gene (7p22.2) | Lymphadenopathy, splenomegaly, autoimmunity, cytopenia, low antibodies, recurrent bacterial infections, chronic viral (EBV, molluscum) infections, B cell lymphoma [35, 36] |
Deregulation of Fas ligand expression caused by IL-12RB1 mutation |
Autosomal recess, LOF mutation in IL12RB1 gene (19p13.11) | Lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10 [37] |
| X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) | LOF mutation in MAGT1 gene (Xq21.1) | Persistent Epstein–Barr virus (EBV) viremia, history of EBV+ lymphoma, a CD4:CD8 T-cell ratio of 1 or less with a normal lymphocyte count or mild to moderate lymphopenia, recurrent sinopulmonary and viral infections, hypogammaglobulinemia, variable antibody response to vaccinations, neutropenia, autoimmunity [38, 39] |
