Autoimmune lymphoproliferative syndrome
Encyclopedia
Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte
apoptosis
. It is a RASopathy
.
) is a rare disorder of abnormal lymphocyte
survival caused by defective Fas
mediated apoptosis
. Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.
Autoimmune disease: The second most common clinical manifestation and one that most often requires treatment.
Revised nomenclature (2010)
New criteria
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. It is a RASopathy
RASopathy
The RASopathies are developmental syndromes caused by germline mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinase that control Signal transduction, including:*Capillary malformation-AV malformation syndrome...
.
Introduction
Autoimmune Lymphoproliferative Syndrome (ALPSALPS
ALPS may refer to:*The Alps, a mountain range spanning Europe*Autoimmune lymphoproliferative syndrome*The Airport Logistics Park of Singapore*The Alps Electric Corporation*A Language for Process Specification...
) is a rare disorder of abnormal lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
survival caused by defective Fas
Fas
Fas can mean the following:* Fas receptor, an important cell surface receptor protein of the TNF receptor family known also as CD95, that induces apoptosis on binding Fas ligand.* Fes, Morocco, the third largest city in Morocco, as an alternate spelling...
mediated apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.
Clinical Manifestations
Lymphoproliferation: The most common clinical manifestation of ALPS is lymphoproliferation, affecting 100% of patients.- LymphadenopathyLymphadenopathyLymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
: >90% of patients present with chronic non-malignant lymphadenopathy. It can be mild to severe, affecting multiple nodal groups. Most commonly presents with massive non-painful hard cervical lymphadenopathy - SplenomegalySplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
: >80% of patients present with clinically identifiable splenomegaly. It can be massive. - HepatomegalyHepatomegalyHepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
: 30-40% of patients have enlarged livers. - Lymphoproliferation tends to present at a young age (median 11.5 months) and may improve with age.
Autoimmune disease: The second most common clinical manifestation and one that most often requires treatment.
- Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.
- Autoimmune Hemolytic Anemia
- Autoimmune NeutropeniaNeutropeniaNeutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
- Autoimmune ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
- Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
- Nervous: Autoimmune cerebellar ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
; Guillain-Barre; Transverse myelitisTransverse myelitisTransverse myelitis is a neurological disorder caused by an inflammatory process of the spinal cord, and can cause axonal demyelination. The name is derived from Greek referring to the "spinal cord", and the suffix -itis, which denotes inflammation... - GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
- Derm: Urticaria
- Pulmonary: Bronchiolitis obliteransBronchiolitis obliteransBronchiolitis obliterans , also called obliterative bronchiolitis and constrictive bronchiolitis , is a rare and life-threatening form of non-reversible obstructive lung disease in which the bronchioles are compressed and narrowed by fibrosis and/or inflammation...
- Renal: Autoimmune glomerulonephritis, nephrotic syndrome
- Nervous: Autoimmune cerebellar ataxia
- Cancer: Secondary neoplasms affect approximately 10% of patients. True prevalence unknown as <20 reported cases of cancer. Most common EBER+ Non-Hodgkin's and Hodgkin's lymphoma
- Unaffected family members with genetic mutations are also at increased risk of developing cancer
Laboratory Manifestations
- Elevated peripheral blood Double Negative T cells (DNTs)
- Required for diagnosis
- Immunophenotype: CD3+/CD4-/CD8-/TCRalpha/beta+
- Measured by flow cytometryFlow cytometryFlow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
: Normal values <2.5% total T cells; <1% of total lymphocytes in peripheral blood - Marked elevations >5% virtually pathognomonic for ALPS
- Mild elevations also found in other autoimmune diseases
- Thought to be cytotoxic T lymphocytes that have lost CD8 expression
- ?Unknown if driver of disease or epiphenomenon
- May be falsely elevated in setting of lymphopenia or falsely decreased with immunosuppressive treatment
- Defective in vitro Fas mediated apoptosis
- Required for diagnosis under old definition. Now can be used to make diagnosis; however, not required to make diagnosis.
- Time and labor intensive assay.
- T cells from patient and normal control supported in culture for >10 days with mitogen stimulation and IL-2 expansion and then exposed to anti-Fas IgM monoclonal antibody
- ALPS patient T cells: Do not die with anti-Fas monoclonal antibody exposure. Normal T cells from unaffected patient do.
- False negative in somatic Fas variant ALPS and FasL variant ALPS
- Genetic mutations in ALPS causative genes (see below)
- Biomarkers
- Polyclonal hypergammaglobulinemiaHypergammaglobulinemiaHypergammaglobulinemia is a medical condition with elevated levels of gamma globulin.It is a type of immunoproliferative disorder.- Types :...
- Elevated serum FASL
- Elevated plasma IL-10 and/or IL-18
- Elevated plasma or serum vitamin B12Vitamin B12Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
- Polyclonal hypergammaglobulinemia
- Autoantibodies: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA.
Classification
Old nomenclature- IA - FasFasFas can mean the following:* Fas receptor, an important cell surface receptor protein of the TNF receptor family known also as CD95, that induces apoptosis on binding Fas ligand.* Fes, Morocco, the third largest city in Morocco, as an alternate spelling...
- IB - Fas ligandFAS ligandFas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
- IIA - Caspase 10Caspase 10Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.-Interactions:Caspase 10 has been shown to interact with FADD, CFLAR, Caspase 8, Fas receptor, RYBP, TNFRSF1A and TNFRSF10B.-External links:*...
- IIB - Caspase 8Caspase 8Caspase 8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase 3.CASP8 orthologs have been identified in numerous mammals for which complete genome data are available...
- III - unknown
- IV - Neuroblastoma RAS viral oncogene homologNeuroblastoma RAS viral oncogene homologNRAS is an enzyme that in humans is encoded by the NRAS gene. It was discovered by researchers at the Institute of Cancer Research, funded by the Imperial Cancer Research Fund , and named NRAS, for its initial identification in human neuroblastoma cells.-External links:*...
Revised nomenclature (2010)
- ALPS-FAS: FasFasFas can mean the following:* Fas receptor, an important cell surface receptor protein of the TNF receptor family known also as CD95, that induces apoptosis on binding Fas ligand.* Fes, Morocco, the third largest city in Morocco, as an alternate spelling...
. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described. - ALPS-sFAS: FasFasFas can mean the following:* Fas receptor, an important cell surface receptor protein of the TNF receptor family known also as CD95, that induces apoptosis on binding Fas ligand.* Fes, Morocco, the third largest city in Morocco, as an alternate spelling...
. Somatic FAS mutations in DNT compartment. 10% of patients - ALPS-FASL: Fas ligandFAS ligandFas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
. Germline FASL mutations. 3 reported cases - ALPS-CASP10: Caspase 10Caspase 10Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.-Interactions:Caspase 10 has been shown to interact with FADD, CFLAR, Caspase 8, Fas receptor, RYBP, TNFRSF1A and TNFRSF10B.-External links:*...
. Germline CASP10 mutation. 2% of patients - ALPS-U: Undefined. 20% of patients
- CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
- RALD: NRASNRASNRAS can be*Neuroblastoma RAS viral oncogene homolog*Australian National Rental Affordability Scheme...
, KRASKRASGTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
. Somatic mutations in NRAS and KRAS in lympocyte comparment. No longer considered a subtype of ALPS but distinct disesase
Diagnostic Algorithm
Old criteria- Required
- Chronic non-malignant lymphoproliferation
- Elevated peripheral blood DNTs
- Defective in vitro Fas mediated apoptosis
New criteria
- Required
- Chronic non-malignant lymphoproliferation (>6 months lymphadenopathy and/or splenomegaly)
- Elevated peripheral blood DNTs
- Accessory
- Primary Accessory
- Defective in vitro Fas mediated apoptosis
- Somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10)
- Secondary Accessory
- Elevated biomarkers
- Plasma sFASL >200pg/ml
- Plasma IL-10 >20pg/ml
- Plasma or serum vitamin B12 >1500ng/L
- Plasma IL-18 >500pg/ml
- Immunohistochemical findings on biopsy consistent with ALPS as determined by experienced hematopathologist
- Autoimmune cytopenias and polyclonal hypergammaglobulinemia
- Family history of ALPS or non-malignant lymphoproliferation
- Elevated biomarkers
- Primary Accessory
- Definitive diagnosis: Required plus one primary accessory criteria
- Probable diagnosis: Required plus one secondary accessory criteria
- Definitive and Probable ALPS should be TREATED THE SAME and patients counseled that they have ALPS if definitive or probable
Treatment
- Mostly commonly directed at autoimmune disease
- Maybe needed to treat bulky lymphoproliferation
- First line therapies
- Corticosteroids
- Very active but toxic with chronic use
- IVIgG
- Not as effective as in other immune cytopenia syndromes
- Corticosteroids
- Second line therapies
- Mycophenolate mofetilMycophenolate mofetilMycophenolate mofetil is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, which is necessary for the growth of T cells and B cells...
(cellcept)- Inactivates inosine monophosphate
- Active in most patients
- Most studied medicine in clinical trials
- Some patients have complete resolution of autoimmune disease
- Some patients have partial responses
- Some patients relapse
- Does not affect lymphoproliferation or reduce DNTs
- Well-tolerated: Side effects: Diarrhea, neutropenia
- Does not require therapeutic drug monitoring
- No drug-drug interactions
- Can cause hypogammaglobulinemia (transient) requiring IVIgG replacement
- Consider PCP prophylaxis but usually not needed
- Most commonly used agent in patients who require chronic treatment based on tolerabilty and efficacy
- SirolimusSirolimusSirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
(rapamycin, rapamune)- mTOR (mammalian target of rapamycinMammalian target of rapamycinThe mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
) inhibitor - Active in most patients
- Second most studied agent in clinical trials
- Most patients have complete resolution of autoimmune disease (>90%)
- Most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%)
- Some patients have near complete response (disease flares with viral illness)
- Some patients have partial responses (most commonly patients with non hematologic autoimmune disease)
- Most patients have elimination of peripheral blood DNTs
- mTOR/Akt/PI3K pathway may be activated in abnormal ALPS cells: mTOR inhibitors may be targeted therapy
- May not be as immune suppressive in normal lymphocytes as other agents. Some patients have had improvement in immune function with transition from cellcept to rapamycin
- Not reported to cause hypogammaglobulinemia
- Hypothetically, may have lower risk of secondary cancers as opposed to other immune suppressants
- Always a risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence
- mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. Thus, THEORETICALLY could eliminate malignant clones.
- Requires therapeutic drug monitoring
- Goal serum trough 5-15ng/ml
- Drug-drug interactions
- Well tolerated: Side effects: mucositis, diarrhea, hyperlipidemia, delayed wound healing
- Consider PCP prophylaxis but usually not needed
- Second most commonly used agent in patients that require chronic therapy.
- Better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis
- mTOR (mammalian target of rapamycin
- Other agents:
- Fansidar, mercaptopurine: More commonly used in Europe. Good ancedotal data
- Rituximab: AVOID. Can cause life long hypogammaglobulinemia
- Splenectomy: AVOID. >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis
- Mycophenolate mofetil