Autoimmune Lymphoproliferative Syndrome Canale Smith Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by:

• Chronic splenomegaly—can result in hypersplenism.

• Lymphadenopathy—usually involves cervical and axillary lymph nodes; may undergo waxing and waning of the severity of enlargement; other peripheral and intracavitary lymph nodes may also be enlarged; lymph nodes histologi-cally benign. Significant reduction in lymph node size occurs during certain viral and bacterial infections.

• Expansion of a/p, CD3+, CD4-, CD8- T cells, known as double-negative T cells (a/p-DNT cells).

• Hepatomegaly—also attributed to accumulation of excessive number of lymphocytes and occasionally to autoimmune hepatitis.

• Urticarial rash—with pruritus and immune vasculitis.

Hematologic Findings

• Anemia—due to autoimmune hemolytic anemia (AIHA) or hypersplenism

• Dyserythropoiesis

• Neutropenia—due to autoimmune antibodies

• Thrombocytopenia due to immunologic thrombocytopenic purpura (ITP) or hypersplenism causing platelet pooling and sequestration

• Eosinophilia

• Hypersplenism.

Immunologic Findings

• Renal insufficiency—due to glomerulonephritis attributed to immune deposition of antigen-antibody complexes

• Autoimmune hepatitis

• Uveitis, iridocyclitis

• Other autoantibody production—antiphospholipid, anticardiolipin, and antinuclear antibodies

• Hypergammaglobulinemia—due to defective apoptosis of B cells accompanied by hyper-IgG, hyper-IgA, high, normal, or decreased IgM and elevated IgE levels

• Elevated interleukin-10 (IL-10) levels in plasma due to its increased production by a/p-DNT cells and monocytes; IL-10 levels correlate with disease expression in ALPS

• Increased soluble CD25, CD30, FasL

• Decreased soluble Fas

• Expansion (elevated) a/P-DNT cells (see below)

• Expansion of other lymphocyte subsets: y/5-DNT cells, CD8+ T cells, HLA-DR+ T cells, CD57+ T cells, CD5+ B cells

• Central nervous system involvement—occurs occasionally: organic brain syndrome (mental status changes, headaches, seizures), Guillain-Barre syndrome

• Age—occurs in both children and adults; however, it manifests in the first few years of life.

Pathophysiology

ALPS has been attributed to defective apoptosis (programmed cell death) of lymphocytes, most often arising as a result of mutations in the gene encoding the lymphocyte apoptosis receptor FAS/APO-1/CD95. Because of the failure of the affected lymphocytes to die after their response to antigen has been completed, there is an accumulation and buildup of an excessive number of polyclonal lymphocytes, which leads to hepatosplenomegaly and lymphadenopathy. The mechanism underlying the induction of autoimmunity is unclear at the present time.

There are subtypes of ALPS on the basis of phenotypic and genotypic differences:

ALPS 0: It is caused by complete deficiency of Fas, resulting from homozygous null mutations of fas (TNFRSF-6, tumor necrosis factor receptor superfamily member 6) gene. Clinically, it manifests with lymphoproliferation with or without autoimmune complications. Its mouse mutant model counterpart is lpr/lpr, Fas ko (knock out).

ALPS Ia: This is the most common type of ALPS. It is caused by heterozygous mutations of fas (TNFRSF-6) gene. Mutant Fas exerts a transdominant effect on wildtype Fas. Clinically, it manifests with lymphoproliferation with or without autoimmune complications. Its mouse mutant model counterpart is lpr cg/lprcg. ALPS Ib: It is caused by a dominant mutation of Fas L (Fas ligand). Clinically, it manifests with features of systemic lupus erythematosus and chronic lymphoprolifer-ation. However, it lacks the classical features of ALPS, that is, expansion of DNT cells and splenomegaly. Its mouse mutant counterpart is gld/gld. ALPS II: It is caused by caspase 8 or caspase 10 deficiency. When it is due to caspase 10 deficiency, it is associated with T-, B-, and dendritic cell-proliferation. Clinically, it manifests with severe autoimmune complications. Caspase 8 deficiency is associated with lymphoproliferation and combined immune defects of T- and B-cell activation.

ALPS III: Molecular defect to account for this subtype of ALPS is unknown.

The following criteria have been recommended by the National Institutes of Health (NIH) ALPS Group to diagnose patients with ALPS:

Required criteria:

1. Chronic nonmalignant lymphoproliferation

2. Defective lymphocyte apoptosis in vitro

3. Greater than or equal to 1% TCR a/p+, CD4-, CD8-, T cells (a/p+-DNT cells) in peripheral blood, and/or presence of DNT cells in lymphoid tissue.

Supporting criteria:

1. Autoimmunity/autoantibodies

2. Mutations in TNFRSF6, FasL, or caspase 10 gene.

Mechanism of Autoimmunity

Although the mechanism of autoimmunity is not fully understood, it is known that DNT cells are not responsible for its manifestations. IL-10 is a likely cytokine playing a role in autoimmune manifestations in ALPS. IL-10 induces T-cell differentiation toward the Th2-cell type and these cells in turn stimulate autoreactive B cells to make autoantibodies. IL-10 also causes increased expression of BCL-2 proteins, which contributes to inhibition of the mitochondrial pathway of apoptosis.

The Origin of a/p-DNT Cells

These cells in ALPS originate from cytotoxic CD8+ T cells that are chronically activated in vivo and anergic in vitro. Also, a/p-DNT cells of ALPS express uniform phe-notype. In contrast, the minor population of a/p-DNT cells in healthy individuals contains multiple subpopulations.

Treatment

Hypersplenism: Splenectomy may be indicated.

Pre- and postsplenectomy: Normal precautions are warranted. Avoid splenectomy in children under 2 years of age. Autoimmune disorder (e.g., ITP, AIHA): This should be treated in the standard way as follows.

Prednisone: If prednisone is required for a prolonged period of time, azathioprine or mycophenolate mofetil (MMF), or cyclosporine may be utilized for their prednisone-sparing effect. Occasionally, anti-CD20 antibody (rituximab) and vincristine have been used to treat resistant cases of ITP. Autoimmune neutropenia: G-CSF can be used.

Fansidar (a combination of pyrimethamine 25 mg/sulfadoxine 500 mg per tablet): Has been found to be effective in a few patients. It induces apoptosis in activated lymphocytes through activation of the mitochondrial apoptotic pathway. Correction of hematologic abnormalities, shrinkage of lymphadenopathy, decrease in hepatomegaly and/or splenomegaly, and decrease in serum IL-10 levels occur in some patients. Allogeneic stem cell transplantation is occasionally necessary. Vaccines: It is important to decrease the frequency of infection, which can aggravate ALPS due to the recruitment of lymphocytes. B-cell responses to infections and vaccinations are mostly intact. All routine immunizations and influenza vaccines should be given. B-cell responses to pneumococcal polysaccharides and blood group antigens are abnormal.

Prognosis

Most patients require splenectomy. ALPS improves with age as children become older. The severity of ALPS varies from mild to severe within the same family. This may be because other pathways of apoptosis are compensating for the FAS pathway. The following malignancies have been reported in ALPS families:

Burkitt lymphoma, T-cell-rich B-cell lymphoma, and atypical lymphoma Nodular lymphocyte predominance Hodgkin disease

Breast cancer, lung cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the tongue, and colon cancer.

Most of the cases of lymphoma occur in families with intracellular mutations of TNFRSF-6.

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