CTLA4 Haploinsufficiency Clinical Trial
Official title:
Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies
Primary immune deficiencies (PID) are a group of chronic diseases characterized by recurrent infections. Apart from recurrent infections, in some of PIDs autoimmunity, allergy or malignancy could be accompanied to the diseases. Recently, the advanced sequencing technologies have led to the identification of a growing number of novel PIDs including the immune dysregulation syndromes caused by loss of function mutations in the LRBA (encoding lipopolysaccharide-responsive beige like anchor protein) and CTLA4 (encoding cytotoxic T lymphocyte antigen 4) genes, which are in common associated with autoimmunity in addition to a predisposition to recurrent infections. PIDs with autoimmune components usually tend to have a more protracted clinical course and poorer prognosis rendering early diagnosis and treatment more crucial. The accurate diagnosis largely relies on the molecular diagnosis due to the significant overlaps between the phenotypic expression of these various genetic defects. The project aims to provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients, discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.
Lipopolysaccharide-responsive beige-like anchor (LRBA) and cytotoxic T lymphocyte protein-4
(CTLA-4) deficiencies are primary immunodeficiency characterized by recurrent sinopulmonary
infections with hypogammaglobulinemia, lymphoproliferation and immunodysregulation, which
presents by enteropathy, cytopenias and autoimmune endocrinopathy. LRBA plays a pivotal role
in the intracellular trafficking of by CTLA4 re-routing it away from lysosomal degradation
and back to the cell surface. CTLA-4 is an key immune checkpoint protein that is
constitutively expressed on fork-head box P3 (FOXP3)+ regulatory T (Treg) cells and is also
induced upon activation of conventional T cells. LRBA deficiency results in very low CTLA4
expression, which explains the phenotypic overlap between LRBA and CTLA4 deficient subjects.
Furthermore, reduced Treg cells number and function have been demonstrated in LRBA-deficient
patients. Consequent upon this, LRBA deficiency may manifest as an IPEX like disease with
early onset autoimmunity.
LRBA was originally described as a common variable immune deficiency (CVID)-like disease with
autoimmunity. To date, different agents have been applied in the treatment of LRBA and CTLA4
deficiencies, including corticosteroids, intravenous immunoglobulin therapy (IVIG),
sirolimus, infliximab, rituximab and azathioprine. Some patients also benefit from
hematopoietic stem cell transplantation (HSCT), which can be curative. More recently, studies
have suggested the effectiveness of abatacept, a CTLA4-Ig fusion protein, in controlling
disease-related immune dysregulatory phenotypes. In addition, some biomarkers like soluble
CD25 and circulating T Follicular helper (cTFH) cells were described as useful to monitor
patients' disease activity. Nevertheless, the long-term effectiveness of abatacept is not
well documented. Also, there is no established consensus as to the dose and frequency of
abatacept therapy for the treatment of those diseases and which biomarker is most reliable
for follow up of patients.
Aims of this current study include:
1. Provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and
advanced immunological, genetic and molecular assays and rendering an early targeting
therapy for patients.
2. Discover disease related new pathways and biomarkers that can be helpful during
diagnosis and monitoring abatacept targeted therapy responses.
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