Study of Autoimmune Lymphoproliferative Syndrome (ALPS)

NCT00001350 | Recruiting

• 2 other identifiers: 93006393-I-0063
• Study Type: observational
• Target: 1,200
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the protocol is to allow for patients, and relatives of patients, who may have the newly described autoimmune lymphoproliferative syndrome, to be evaluated at the NIH Clinical Center. This evaluation will include blood and relevant tissue studies along with long-term clinical evaluations to define the biology, inheritance,clinical spectrum, and natural history of this syndrome. The aim of the research is to understand mechanisms involved in the development of expanded numbers of what is typically a rare population of immune cells (CD4-8-/TCRalpha/beta+ T cells, otherwise referred to as double negative T cells), and how these relate to the development of expanded numbers of immune cells and autoimmune (self against self) responses in patients with ALPS. In some cases, we may proivide treatment related to ALPS. These treatments are consistent with standard medical practice. Participants with ALPS will be invited to visit the NIH once a year or more frequently when clinically indicated for the next few years for clinicians and scientists to follow the course of their disease and to manage its complications. Knowledge gained from these studies provides important insights into the mechanisms of autoimmunity, the thymus gland, and the role that the immune system and genetics plays in ALPS. Autoimmune lymphoproliferative syndrome is a rare disease that affects both children and adults. Each of these three words helps describe the main features of this condition. The word autoimmune (self-immune) identifies ALPS as a disease of the immune system. The tools used to fight germs turn against our own cells and cause problems. The word lymphoproliferative describes the unusually large numbers of white blood cells (called lymphocytes (stored in the lymph nodes and spleens of people with ALPS. The word syndrome refers to the many common symptoms shared by ALPS patients. One of the causes of ALPS is defective apoptosis, or said another way, an individual has an abnormality in how well lymphocytes (immune cells) die when they are instructed to do so. It is normal for lymphocytes to disintegrate (e.g., die) when they have done their job. In people with ALPS and in some of their affected relatives, the genetic message for the cells to die is altered: the message is not received and the cells do not die when they should. As a result, people with ALPS develop an enlarged spleen, liver and lymph glands, along with a range of other problems involving white blood cell counts and overactive immune responses (autoimmune disease). Some patients have an increased risk of developing lymphatic cancers (lymphoma). Provided is a description of eligible study candidates:

• a medical history of an enlarged spleen and/or enlarged lymph nodes over an extended period of time (past and/or current).
• defective lymphocyte apoptosis, in vitro.
• greater than or equal to 1 percent TCR alpha/beta+CD4-8- peripheral blood T cells.
• Relatives (any age) of patients and normal controls (18-65).
• Healthy normal volunteers will also be enrolled to provide data on normal cell behavior for comparison with patients.

Conditions

Benign Lymphoproliferative Disorder

Keywords

Immunoregulation; T Cell Receptor Alpha/Beta; Lymphoproliferation; Fas; Autoimmune Disease; Natural History

Outcome Measures

Primary Outcomes (1)

• Elucidate the mechanism of immune-dysregulation leading to ALPS and develop targeted treatments

  Improvement of underlying immune-dysregulation

  Median follow up of 25 years

Study Arms (1)

1

ALPS patients and relatives of all ages

Eligibility Criteria

• Age: Up to 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

ALPS patients and relatives to include males and females of all ages

You may qualify if:

• In order to be eligible to enroll as a potential patient participant in the initial evaluation, an individual must meet all of the following criteria:
• Aged 0 to 99 years (must be greater than or equal to 3 years to be seen at the NIH Clinical Center).
• A history of chronic (\>6 months) lymphadenopathy and/or splenomegaly (exception for newborns with family history of ALPS related disorders).
• Willingness to allow blood, tissue, and other samples to be stored.
• In order to be eligible to enroll as a relative for the screening portion of this study, an individual must meet all of the following criteria:
• Aged 0 to 99 years (must be greater than or equal to 3 years to be seen at the NIH Clinical Center).
• Extended family members, identified as blood relatives, of an ALPS patient.
• Able to provide informed consent.
• Willingness to allow blood, tissue, and other samples to be stored.
• In order to be eligible to participate in the natural history study as a patient with ALPS, an individual must meet all of the following criteria:
• Aged 0 to 99 years (must be greater than or equal to 3 years to be seen at the NIH Clinical Center).
• To be considered as having ALPS, patients must have elevated CD3+TCR alpha/beta+ CD4-8-peripheral blood DNT cells (equal to or greater than 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts.
• A history of chronic (\>6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly (exception for newborns with family history of ALPS related disorders).
• Willingness to allow blood, tissue and other samples to be stored.
• Patients with RALD who present with autoimmunity, lymphadenopathy, and/or splenomegaly, with elevated or normal DNTs and somatic mutations in NRAS and KRAS.29-32

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (4)

• Price S, Shaw PA, Seitz A, Joshi G, Davis J, Niemela JE, Perkins K, Hornung RL, Folio L, Rosenberg PS, Puck JM, Hsu AP, Lo B, Pittaluga S, Jaffe ES, Fleisher TA, Rao VK, Lenardo MJ. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014 Mar 27;123(13):1989-99. doi: 10.1182/blood-2013-10-535393. Epub 2014 Jan 7.

  PMID: 24398331 BACKGROUND

• Xie Y, Pittaluga S, Price S, Raffeld M, Hahn J, Jaffe ES, Rao VK, Maric I. Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation. Haematologica. 2017 Feb;102(2):364-372. doi: 10.3324/haematol.2015.138081. Epub 2016 Oct 20.

  PMID: 27846610 DERIVED

• Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson ED, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, Perminow G, Rao VK, O'Connell MP, Price S, Su HC, Butrick M, McElwee J, Hughes JD, Willet J, Swan D, Xu Y, Santibanez-Koref M, Slowik V, Dinwiddie DL, Ciaccio CE, Saunders CJ, Septer S, Kingsmore SF, White AJ, Cant AJ, Hambleton S, Cooper MA. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015 Jan 22;125(4):591-9. doi: 10.1182/blood-2014-09-602763. Epub 2014 Oct 30.

  PMID: 25359994 DERIVED

• Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011 Nov 24;118(22):5741-51. doi: 10.1182/blood-2011-07-325217. Epub 2011 Sep 1.

  PMID: 21885601 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Autoimmune Lymphoproliferative Syndrome, Type IA; Autoimmune Diseases

Condition Hierarchy (Ancestors)

Immune System Diseases

Study Officials

• V. Koneti Rao, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alanvin D Orpia, R.N.

CONTACT

(240) 550-3663; alanvin.orpia@nih.gov

V. Koneti Rao, M.D.

CONTACT

(301) 496-6502; kr191c@nih.gov

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: November 4, 1999
• Study Start: May 13, 1993
• Last Updated: April 29, 2026

Record last verified: 2026-01-07

Locations

US (1)