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]
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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.
