Autoimmune lymphoproliferative syndrome (ALPS) is a form of
lymphoproliferative disorder
Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised ...
(LPDs). It affects
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
It is a rare genetic disorder of abnormal
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
survival caused by defective
Fas mediated
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
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.
Signs and symptoms
All people with ALPS have signs of lymphoproliferation, which makes it the most common clinical manifestation of the disease. The increased proliferation of lymphoid cells can cause the size of lymphoid organs such as the
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
s and
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . to increase (
lymphadenopathy and
splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulatin ...
, present in respectively over 90% and over 80% of patients). The
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
is enlarged (
hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
) in 30–40% of patients.
Autoimmune disease is the second most common clinical manifestation and one that most often requires treatment. The most common autoimmune presentations include autoimmune cytopenias, which can be mild to very severe and intermittent or chronic.
These include
autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of ...
,
autoimmune neutropenia, and
autoimmune thrombocytopenia
Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of othe ...
. Other autoimmune manifestations can be similar to
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(least common, affecting <5% of patients). Manifestations within the nervous system can include autoimmune
cerebellar ataxia
Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias.
Cerebellar ataxia can occur as a result of many diseases and may present with symptom ...
,
Guillain–Barré syndrome
Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain oft ...
, and
transverse myelitis
Transverse myelitis (TM) is a rare neurological condition wherein the spinal cord is Inflammation, inflamed. The adjective ''wikt:transverse#Adjective, transverse'' implies that the spinal inflammation (myelitis) extends horizontally throughout ...
. Manifestations in the gastrointestinal system can include
atrophic gastritis
Atrophic gastritis is a process of chronic inflammation of the gastric mucosa of the stomach, leading to a loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues. As a result, the stomach's secretion o ...
, and
autoimmune hepatitis
Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the liv ...
,
esophagitis
Esophagitis, also spelled oesophagitis, is a disease characterized by inflammation of the esophagus. The esophagus is a tube composed of a mucosal lining, and longitudinal and circular smooth muscle fibers. It connects the pharynx to the stomach; s ...
,
colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualification ...
, and
pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
. Other manifestations can affect the skin (
hives
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
), lungs (
bronchiolitis obliterans), or kidneys (autoimmune
glomerulonephritis
Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...
and
nephrotic syndrome).
Another sign are cancers such as
Hodgkin and
non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
s, which appear to be increased,
possibly due to
Epstein–Barr virus
The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus.
It is b ...
-encoded RNA-positivity. Some carcinomas may occur. Unaffected family members with genetic mutations are also at an increased risk of developing cancer.
Genetics
This condition is usually caused by mutations in the FAS gene. Rarely cases due to mutations in other genes including the
FAS ligand gene have been reported.
[Magerus-Chatinet A, Stolzenberg MC, Lanzarotti N, Neven B, Daussy C, Picard C, Neveux N, Desai M, Rao M, Ghosh K, Madkaikar M, Fischer A, Rieux-Laucat F (2012) Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. J Allergy Clin Immunol] The disease is inherited in an autosomal dominant manner, but it shows incomplete penetrance with up to 40% of people with a FAS mutation not showing symptoms.
[ Autoimmune Lymphoproliferative Syndrome (ALPS) Causes. (2019, April 19). NIH: National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/autoimmune-lymphoproliferative-syndrome-causes ]
Diagnosis
Diagnostic algorithm
The old diagnostic criteria for the illness included:
Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis.
The new criteria
require chronic non-malignant lymphoproliferation (over six months lymphadenopathy and/or splenomegaly), elevated peripheral blood DNTs. A primary accessory in diagnosis is defective in vitro Fas mediated apoptosis and somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10).
The secondary accessory in diagnosis are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma IL-10 >20 pg/ml, plasma or serum vitamin B
12 >1500 ng/L, Plasma IL-18 >500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS as determined by an experienced hematopathologist. Another sign is autoimmune cytopenias and polyclonal hypergammaglobulinemia and a family history of ALPS or non-malignant lymphoproliferation.
A definitive diagnosis is chronic non-malignant lymphoproliferation and/or elevated peripheral blood DNTs plus one primary accessory criterion. A probable diagnosis is the same but with one secondary accessory criterion.
Classification
2003 nomenclature
* IA -
Fas
* IB -
Fas ligand
* IIA -
Caspase 10
Caspase-10 is an enzyme that, in humans, is encoded by the ''CASP10'' gene.
This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execut ...
* IIB -
Caspase 8
Caspase-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. These unique orthologs are also prese ...
* III - unknown
* IV -
Neuroblastoma RAS viral oncogene homolog
NRAS is an enzyme that in humans is encoded by the ''NRAS'' gene. It was discovered by a small team of researchers led by Robin Weiss at the Institute of Cancer Research in London. It was the third ''RAS'' gene to be discovered, and was named ''N ...
Revised nomenclature (2010)
* ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.
* ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment.
10% of patients
* ALPS-FASL:
Fas ligand. Germline FASL mutations. 3 reported cases
* ALPS-CASP10:
Caspase 10
Caspase-10 is an enzyme that, in humans, is encoded by the ''CASP10'' gene.
This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execut ...
. 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:
NRAS,
KRAS
''KRAS'' (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...
. Somatic mutations in NRAS and KRAS in lymphocyte compartment. No longer considered a subtype of ALPS but distinct disease
Treatment
Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include
corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.
Second line therapies include:
mycophenolate mofetil
Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liv ...
(cellcept)
which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy. It may cause hypogammaglobulinemia (transient) requiring IVIgG replacement.
Sirolimus
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
(rapamycin, rapamune) which is a mTOR (
mammalian target of rapamycin
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
) inhibitor
can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%)
With this treatment most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%) and have elimination of peripheral blood DNTs. Sirolimus 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
and it has not been reported to cause hypogammaglobulinemia. Hypothetically, Sirolimus may have lower risk of secondary cancers as opposed to other immune suppressants and requires therapeutic drug monitoring. It is the second most commonly used agent in patients that require chronic therapy. It is mostly well tolerated (though side effects include mucositis, diarrhea, hyperlipidemia, delayed wound healing) with drug-drug interactions. It has better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis. A risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence. Its mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. The Goal serum trough is 5–15 ng/ml and can consider PCP prophylaxis but usually not needed.
Other treatments may include drugs like
Fansidar
Sulfadoxine/pyrimethamine, sold under the brand name Fansidar, is a combination medication used to treat malaria. It contains sulfadoxine (a sulfonamide) and pyrimethamine (an antiprotozoal). For the treatment of malaria it is typically used a ...
,
mercaptopurine: More commonly used in Europe. Another is
rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric pa ...
but this can cause protracted hypogammaglobulinemia
and a
splenectomy
A splenectomy is the surgical procedure that partially or completely removes the spleen. The spleen is an important organ in regard to immunological function due to its ability to efficiently destroy encapsulated bacteria. Therefore, removal of ...
but there is a >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis
References
External links
{{Medical resources
, DiseasesDB = 33425
, ICD10 =
, ICD9 = {{ICD9, 279.41
, ICDO =
, OMIM = 601859
, OMIM_mult = {{OMIM, 603909, , none
, MedlinePlus =
, eMedicineSubj =
, eMedicineTopic =
, MeshID =
, Orphanet = 3261
Lymphocytic immune system disorders
RASopathies
Syndromes with tumors