Autoimmune Lymphoproliferative Syndrome

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Autoimmune lymphoproliferative syndrome (ALPS) is characterized by nonmalignant lymphadenopathy, splenomegaly, and autoimmune cytopenias. [1] In 1995, defective lymphocyte apoptosis secondary to mutations in the FAS gene was identified as a molecular basis for ALPS. [2] Other ALPS-associated genetic defects in the apoptotic pathway have since been identified. ALPS is the first disease known to be caused by a primary defect in programmed cell death and is the first autoimmune disease with a defined genetic basis. [3]

An illustrative case of ALPS is as follows:

A 10-year-old male presented with a history of lymphadenopathy, splenomegaly, and onset of multilineage cytopenias as an infant, with subsequent splenectomy at age 13 months

After undergoing the splenectomy, the patient developed pneumococcal meningitis, which led to hearing loss that required a cochlear implant

Subsequently, the patient experienced several episodes of pneumococcal sepsis, chronic osteomyelitis, profound neutropenia, vasculitis, autoimmune hemolytic anemia, and thrombocytopenia, with many hospitalizations and intensive care unit (ICU) admissions for treatment of these complications

This patient’s repeated infections with encapsulated organisms highlight the importance of maintaining the spleen in ALPS patients, if possible. The constellation of lymphadenopathy, splenomegaly, and autoimmune cytopenias necessitating long-term immunosuppressive treatment with mycophenolate mofetil makes diagnosis and management of these patients quite challenging.

The essential role Fas plays in maintaining lymphocyte homeostasis and peripheral immune tolerance to prevent autoimmunity was first clarified 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, has been shown to represent a failure of apoptotic mechanisms. It is most often associated with heterozygous mutations in the gene that encodes the Fas protein tumor necrosis factor receptor superfamily 6 (TNFRSF6) and other related effector proteins that regulate lymphocyte survival. [6]

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. This is known as the extrinsic pathway of apoptosis. Mutations have been identified in each of the genes that code for Fas, FasL, caspase 8 and caspase 10 (see the image below). [7]

An NRAS mutation has been identified that represents the first identified case of ALPS resulting from a defect in the intrinsic, or mitochondrial, apoptotic pathway. [8] The nomenclature for the various types of ALPS or ALPS-related disorders is determined on the basis of the genetic mutation present in each individual

Autoimmune lymphoproliferative syndrome (ALPS) and ALPS-related disorders classification

Patients meeting diagnostic criteria for ALPS in whom no genetic mutation can be identified are classified as ALPS–undetermined. ALPS-related disorders have features similar to those of ALPS but have several additional characteristics, such as additional defective T-, B-, and natural killer (NK)-cell activation in caspase 8 deficiency state (CEDS), or are missing required diagnostic features, such as an elevated number of DNT cells, as seen in RAS-associated autoimmune leukoproliferative disease (RALD). [9]

Defective apoptosis results in inappropriate persistence and accumulation of autoreactive or potentially oncogenic lymphocytes, leading to splenomegaly and lymphadenopathy with an increased risk of lymphoma. The multilineage cytopenias often noticed in ALPS result from splenic sequestration, as well as from underlying autoimmune processes. [10]

Another characteristic feature of ALPS is an elevated number of DNT cells (see above). Although the origin of this cell population is unclear, a study that examined the TCR of DNT cells in ALPS suggested that these may represent oligoclonally expanded CD8+ T cells that subsequently lost CD8 expression. The significance of these DNT cells is also not fully understood but has been associated with elevated interleukin (IL)–10 levels and serum immunoglobulin levels in patients with ALPS. [11]

Investigation of family members of ALPS patients has revealed a population with identical genetic mutations but with absent or mild forms of the disease that in many cases fall short of the case definition of ALPS. This finding supports the idea that the pathophysiology of ALPS is multifactorial, with an autosomal dominant inheritance pattern and variable penetrance. [12]

For most cases of ALPS, the genetic mutation has been identified in the extrinsic apoptosis pathway or the intrinsic pathway. [8] Although some patients have no identifiable mutation that leads to their defective lymphocyte apoptosis, they may still meet the diagnostic criteria for ALPS or an ALPS-related disorder (see Workup).

In patients with ALPS, the disease process can often be explained by the failure to eliminate redundant lymphocyte populations properly. As noted (see above), lymphocytes that are potentially autoreactive or oncogenic predispose these patients to the development of autoimmune diseases and lymphoma. [13]

The initial presentation of autoimmune lymphoproliferative syndrome (ALPS) is often that of persistent lymphadenopathy or splenomegaly followed by an autoimmune disease such as idiopathic thrombocytopenic purpura (ITP) or hemolytic anemia in an otherwise healthy child. [12] To meet the case definition of ALPS, a patient must have chronic, nonmalignant lymphadenopathy or splenomegaly that lasts for 6 months or longer.

Associated multilineage cytopenias due to autoantibodies or splenic sequestration can lead to petechiae, bleeding, pallor, icterus, fatigue, and recurrent infections; the latter are mostly due to neutropenia. A family history of similar disorders may be noted; these are usually inherited in an autosomal dominant fashion. A thorough review of a patient’s extended family for a history of adenopathy, cytopenias, splenectomies, or lymphoma can provide helpful information and clues in diagnosing ALPS.

Careful attention to the development of systemic B symptoms (eg, fever, drenching night sweats, pruritus, and weight loss) is important for cancer surveillance in those at high-risk for B cell lymphoma. Some of the patients also develop autoimmune diseases that affect other organs (eg, autoimmune hepatitis, glomerulonephritis, uveitis, and Guillain-Barre syndrome).

The mortality and morbidity of ALPS vary widely. The major determinants of prognosis in patients diagnosed with ALPS include the following:

Severity of autoimmune disease (particularly autoimmune cytopenias)

Hypersplenism

Asplenia-related sepsis

Development of lymphoma

Addressing these serious conditions with proper surveillance and education is vital for an optimal prognosis. Patients with mutations of the intracellular region of the Fas protein have a significantly increased risk of developing lymphoma and warrant the most diligent long-term surveillance. Despite the numerous potentially serious complications, the overall prognosis for patients with ALPS is good.

Many patients are expected to live a normal lifespan, with few clinical complications. [7] However, a significant number of patients develop childhood-onset life-threatening cytopenias, which necessitate interventions such as hospitalization, immunosuppressive therapy, blood transfusion, antibiotic therapy, or splenectomy. These cytopenias are often chronic and refractory.

As pediatric ALPS patients develop into adolescents and young adults, the degree of adenopathy (particularly visible adenopathy) tends to decrease. In the authors’ experience, this is a good thing to discuss with the patients and their families, particularly during adolescence, when visible adenopathy can be particularly distressing.

As with all chronic diseases, appropriate management of ALPS requires continual reinforcement and education regarding matters of adequate nutrition and control of potential adverse effects of medications. In addition, as with many chronic diseases with an onset in childhood, adolescence and early adulthood may provide the additional treatment challenge of poor compliance with prescribed medications. Individual responsibility should be encouraged and emphasized by the treatment team.

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Luke M Webb, MD Staff Physician, Department of Allergy and Immunology, Evans Army Community Hospital

Luke M Webb, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

David J Schwartz, MD Staff Physician, Department of Allergy and Immunology, Eisenhower Army Medical Center

David J Schwartz, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

V Koneti Rao, MD, FRCPA Staff Clinician, Lymphocyte Clinical Genomics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

V Koneti Rao, MD, FRCPA is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter’s University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Acknowledgments

The authors acknowledge Drs Kip Hartman and Margaret Merino of the Pediatric Hematology and Oncology Department at the Walter Reed Army Medical Center for the use of their clinical expertise and patient photographs in this article. In addition, the authors thank Dr Scott Whitworth of the Department of Radiology at Walter Reed Army Medical Center for his assistance with positron emission tomography (PET) imaging. Finally, the authors also express thanks to the patients and parents who granted permission to use these photographs.

This research was supported by the Intramural Research Program of the National Institutes of Health. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the US Government.

Autoimmune Lymphoproliferative Syndrome

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