Study of Autoimmune Lymphoproliferative Syndrome (ALPS)
Study of Autoimmune Lymphoproliferative Syndrome (ALPS)
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:

 1. Any patient with ALPS, male or female and of any age. As a patient with ALPS, candidates
 must have:

 -  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.

 2. Relatives (any age) of patients and normal controls (18-65).

 3. Healthy normal volunteers will also be enrolled to provide data on normal cell behavior
 for comparison with patients.

 Additional information regarding ALPS and the research being conducted at the National
 Institutes of Health is available at the following World Wide Web (e.g., Internet) locations:

 http://www.niaid.nih.gov/publications/alps/

 http://www.nhgri.nih.gov/DIR/GMBB/ALPS/.
The purpose of this family based natural history protocol is to allow for patients, and
 relatives of patients to be screened for Autoimmune Lymphoproliferative Syndrome (ALPS) and
 related disorders of apoptosis, RAS associated leukoproliferative disorder (RALD). Patients
 and relatives will be evaluated at the NIH Clinical Center if they meet the eligibility
 criteria. This evaluation will include blood and relevant tissue studies along with long-term
 clinical evaluation to define the biology, inheritance, clinical spectrum, and natural
 history of this syndrome. The aim of the research studies is to elucidate mechanisms
 underlying the immune dysregulation due to defective apoptosis in these patients. Knowledge
 gained from these studies provides important insights into the mechanisms of autoimmunity,
 normal thymic and extra thymic T cell differentiation, TCR repertoire selection, and
 lymphomagenesis. Medically indicated management of ALPS-related autoimmune disease and
 cytopenias will also be considered and provided, using standard of care treatments.
-  INCLUSION CRITERIA:

 A. ALPS Natural History sample size and demographics:

 Study size: up to 1000 patients, patients, relatives and normal controls.

 Sex Distribution: Male and female

 Age range: All ages acceptable

 B. Eligibility Criteria for Natural History Study:

 1. To be considered as having ALPS, patients must elevated TCR alpha/beta+ CD4-8-
 peripheral blood DNT cells (equal to or greater than 1.5 percent of total lymphocytes
 or 2.5 percent of CD3+ lymphocytes) in the setting of normal or evalted lymphocyte
 counts.

 2. A history of chronic (greater than 6 months) non-malignant, non-infectious
 lymphadenopathy and/or splenomegaly.

 3. Willingness to allow blood, tissue and other samples to be stored.

 4. Patients with RALD (RAS associated leukoproliferative disorders) who present with
 autoimmunity, lymphadenopathy and/or splenomegaly, with elevated or normal DNT s and
 somatic mutations in NRAS and KRAS

 C. Eligibility Criteria for Screening potential patients:

 1. A history of chronic (greater than 6 months) lymphadenopathy and/or splenomegaly.

 2. Willingness to allow blood, tissue and other samples to be stored.

 D. Screening criteria for ALPS Relatives:

 1. Extended family members of an ALPS patient are eligible for genetic screening to
 determine if they carry the mutation found in their family.

 2. Willingness to allow blood, tissue and other samples to be stored.

 E. Eligibility of special populations:

 1. Women who are pregnant or breast feeding are eligible to enroll as probands or
 relatives. However, certain obstetric issues may pose a safety risk for travel and
 evaluation here. Eligibility for this group will be determined on a case by case basis by
 the PI. This protocol is not actively seeking women who are pregnant

 F. 1. Apheresis will be done only on healthy volunteers or patients with ALPS who have
 adequate peripheral venous access. Women of childbearing age must have a negative pregnancy
 test within 24 hours of the procedure and must not be breast-feeding.

 EXCLUSION CRITERIA:

 1. Any condition that the Principal Investigator deems to be non-conducive to the research
 goals of the study.