Idiopathic CD4 Lymphocytopenia Clinical Trial
Official title:
Analysis of Clinical and Immunological Characteristics, as Well as Pathophysiological Mechanisms in a French Cohort of Patients With Idiopathic CD4 Lymphocytopenia
Definition: Idiopathic CD4+ T lymphocytopenia (ICL) is an immune deficiency first described
in 1992 and characterized by the US Centers for Disease Control (CDC) as absolute CD4+
T-lymphocyte count < 300/mm3 or < 20% of total T cells on more than one cell count; no
evidence of infection with HIV-1/2 or human T-cell lymphotropic 1/2 (HTLV-1/2); and lack of a
defined immune-deficiency disease or therapy for lymphocytopenia. Epidemiologic, clinical and
immunological characteristics of the syndrome were described in 1993 and ICL is now
considered a heterogeneous syndrome not caused by an infectious agent. Patients with ICL may
show opportunistic infections such as disseminated Cryptococcus neoformans infection,
Pneumocystis jiroveci pneumonia and John Cunningham (JC) virus infection as a result of
profound cell-mediated immune-response deficiency.
Few studies have focused on the pathophysiology of ICL. CD4+ T-lymphocyte phenotyping
revealed increased CD95 expression that could be responsible for excess apoptosis leading to
lymphocytopenia. Moreover, the membrane expression of C-X-C chemokine receptor type 4 (CXCR4)
was found impaired in T lymphocytes with ICL, and CXCR4 trafficking was improved with
interleukin 2 (IL-2) treatment in some patients. Recently, mutations in nunc119, MAGT1 and
Rag were found associated with CD4+ T lymphocytopenia. In a prospective study of 39 patients,
CD8+ T lymphocytopenia (<180/mm3) and degree of CD4+ T-cell activation measured by human
leukocyte antigen DR (HLA-DR) expression was found associated with poor prognosis.
ICL is a heterogeneous disorder often associated with deficiencies in CD8+, CD19+, and/or NK
cells. Long-term prognosis may be related to initial CD4+ and NK cell deficiency.
Larger studies are needed to better identify the patients who might benefit from IL-2
therapy. This is why the investigators conduct the Lympho-4 study, in which the investigators
plan to include 200 patients with a suspected/proven diagnosis of ICL.
Definition. Idiopathic CD4+ T lymphocytopenia (ICL) is an immune deficiency first described
in 1992 and characterized by the US Centers for Disease Control (CDC) as absolute CD4+
T-lymphocyte count < 300/mm3 or < 20% of total T cells on more than one cell count; no
evidence of infection with HIV-1/2 or human T-cell lymphotropic 1/2 (HTLV-1/2); and lack of a
defined immune-deficiency disease or therapy for lymphocytopenia.
ICL is a heterogeneous disorder often associated with deficiencies in CD8+, CD19+, and/or NK
cells. Thus, ICL does not correspond to a unique disease but more probably to a number of
different conditions with distinct underlying mechanisms. This is why the investigators
decided to launch the Lympho-4 study, in which the investigators plan to include 200 patients
with a suspected/proven diagnosis of ICL.
The aim of the study will be to
1. identify patients in whom the diagnosis of ICL is confirmed using an algorithm developed
by a group of multidisciplinary experts.
2. describe and compare clinical, immunological and follow up characteristics of patients
in whom the diagnosis of ICL was confirmed vs patients in whom the diagnosis of ICL is
not confirmed.
The investigators will also investigate :
Lymphocyte subpopulations including analysis of differentiation and activation of T and B
lymphocytes, immortalisation of cell lineages with virus Epstein Barr virus, high rate genome
wide genetic screening, investigation of mutations associated with identified primary immune
deficiencies (adenosine deaminase et class II MHC), constitution of a biobank of frozen
plasma and serum samples ; investigation of the thymic volume by performing a CT scan.
Depending on clinical presentation and based on previous data obtained by our group, the
investigators will investigate the immune responses against Human papilloma virus (HPV),
Cryptococcus neoformans,implication of chemokines involved in lymphocyte migration (CXCR4 and
CCR7 receptors) and signalisation in response to cytokines controlling LT CD4+ homeostasis
(IL-7 et IL-2).
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