Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome
OMIM	601859 603909
DiseasesDB	33425 Template:DiseasesDB2

Editor-In-Chief: David Teachey, MD [1]

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Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis.

Introduction

Autoimmune Lymphoproliferative Syndrome (ALPS) 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.

Clinical Manifestations

1. Lymphoproliferation: The most common clinical manifestation of ALPS is lymphoproliferation, affecting 100% of patients.

  A. Lymphadenopathy: >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
  B. Splenomegaly: >80% of patients present with clinically identifiable splenomegaly. It can be massive.
  C. Hepatomegaly: 30-40% of patients have enlarged livers.
  Lymphoproliferation tends to present at a young age (median 11.5 months) and may improve with age.

2. Autoimmune disease: The second most common clinical manifestation and one that most often requires treatment.

  A. Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.
     1. Autoimmune Hemolytic Anemia 
     2. Autoimmune Neutropenia
     3. Autoimmune Thrombocytopenia
  B. Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
     Nervous: Autoimmune cerebellar ataxia; Guillain-Barre; Transverse myelitis
     GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
     Derm: Urticaria
     Pulmonary: Bronchiolitis obliterans
     Renal: Autoimmune glomerulonephritis, nephrotic syndrome

3. Cancer: Secondary neoplasms affect approximately 10% of patients. True prevalance unknown as <20 reported cases of cancer. Most common EBER+ non-hodgkins and hodgkins lymphoma

  Unaffected family members with genetic mutations are also at increased risk of developing cancer

Laboratory Manifestations

1. Elevated peripheral blood Double Negative T cells (DNTs)

  Required for diagnosis
  Immunophenotype: CD3+/CD4-/CD8-/TCRalpha/beta+
  Measured by flow cytometry: Normal values <2.5% total T cells; <1% of total lymphocytes in peripheral blood
  Marked elevations >5% virtually pathognomic 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

2. 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

3. Genetic mutations in ALPS causative genes

  FAS
  FASL 
  CASP10

4. Biomarkers

  Polyclonal hypergammaglobulinemia
  Elevated serum FASL
  Elevated plasma IL-10 and/or IL-18

5. Autoantibodies: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA.

Among the possible symptoms are splenomegaly and hepatomegaly.

Classification

Types include:

• IA - Fas receptor (this form is the most common)
• IB - Fas ligand
• IIA - Caspase 10
• IIB - Caspase 8
• III - unknown
• IV - Neuroblastoma RAS viral oncogene homolog