PURPOSE OF THE STUDY.
Identify the possible genetic basis among a group of patients presenting with a constellation of findings including hypogammaglobulinemia, CD4 T-cell lymphopenia, autoimmune cytopenias, and lymphocytic infiltration of nonlymphoid organs (brain, lung, gastrointestinal tract).
A total of 23 patients with varying combinations of the findings noted above were selected from a larger cohort of patients referred to the National Institutes of Health for possible autoimmune lymphoproliferative syndrome (ALPS; based on the presence of lymphadenopathy and autoimmune cytopenias).
The patients studied had ALPS ruled out based on functional and genomic studies. Because of their common clinical phenotype, the patients were studied using ex vivo immune function assays as well as evaluated genetically by either whole exome sequencing or selected gene sequencing using the Sanger method.
Six of the 23 patients evaluated from 4 families were found to have heterozygous mutations in the gene encoding the protein cytotoxic lymphocyte antigen (CTLA)-4. The patients carrying these mutations were found to have decreased numbers as well as decreased function of T-regulatory (Treg) cells. In addition, intracellular CTLA-4 expression in Treg cells was diminished in the patient’s cells. Additional findings included hyperproliferation of T cells, a finding that was recapitulated by knocking down CTLA-4 using siRNA in normal cells and abrogated by providing normal CTLA-4 through reconstituting CTLA-4 using vector transfection of patient cells. Finally, patient B cells showed a progressive decline in numbers, an increase in autoreactive cells, and decreased ex vivo proliferation.
CTLA-4 is a critical immunoregulatory protein for normal T-cell and B-cell homeostasis. In these patients, a single normal allele was insufficient to prevent lymphoid infiltration into the lungs, brain, or gastrointestinal tract or inhibit the development of autoimmune cytopenias. Interestingly, this defect showed incomplete penetrance, and some family members (n = 3) carrying the same mutation as affected patients were either healthy or had only minimal symptoms.
These patients add to a growing list of newly defined genetic defects that are at the crossroads of immune deficiency and immune dysregulation. In this case, there is evidence that some of the findings, such as the decline in B cells, may progress over time. It is interesting that the clinical findings in these patients actually mirror complications seen with newly designed therapies in cancer immunotherapy aimed at blocking CTLA-4 by using neutralizing monoclonal antibody. It is also possible that the patients with heterozygous CTLA4 mutations could benefit from the use of a CTLA-4 mimetic (CTLA-4-Ig). The finding of incomplete penetrance fits with the findings of a similar phenomenon in other autosomal dominant immune dysregulation syndromes such as ALPS.
- Copyright © 2015 by the American Academy of Pediatrics