Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

Abstract

METHODS.We hybridized 34 and 51 ICL patients' sera to a 9,000-human-proteome array and to a 128-known-autoantigen array, respectively. Using a flow-based method, we characterized the presence of anti-lymphocyte Abs in the whole cohort of 72 patients, as well as the Ab functional capability of inducing Ab-dependent cell-mediated cytotoxicity (ADCC), complement deposition, and complement-dependent cytotoxicity (CDC). We tested ex vivo the activation of the classical complement pathway on ICL CD4 + T cells. RESULTS.All ICL patients had a multitude of autoantibodies mostly directed against private (not shared) targets and unrelated quantitatively or qualitatively to the patients' autoimmune disease status. The targets included lymphocyte intracellular and membrane antigens, confirmed by the detection by flow of IgM and IgG (mostly IgG 1 and IgG 4 ) anti-CD4 + cell Abs in 50% of the patients, with half of these cases triggering lysis of CD4 + T cells. We also detected in vivo classical complement activation on CD4 + T cells in 14% of the whole cohort. CONCLUSION.Our data demonstrate that a high prevalence of autoantibodies in ICL, some of which are specific for CD4 + T cells, may contribute to pathogenesis, and may represent a potentially novel therapeutic target. TRIAL REGISTRATION. ClinicalTrials.gov NCT00867269.

Co-Occurrence of ANCA-Associated Vasculitis and Sjögren’s Syndrome in a Patient With Acromegaly: A Case Report and Retrospective Single-Center Review of Acromegaly Patients

“…In order to explore the presence of additional autoantibodies as an indication of dysregulated immunity, an experimental autoantibody microarray with 128 different autoantigens was used ( 7 ). Besides the anti-SSA/Ro and anti-MPO antibodies which had already been identified as part of the routine clinical work-up ( Table S1 ), IgG antibodies against a broad spectrum of additional antigens was found in a sample taken at the time of AAV diagnosis ( Figures S1 and S2 ).…”

Expanding mechanistic insights into the pathogenesis of idiopathic CD4+ T cell lymphocytopenia

“…The clinical observations by Perez-Diez and Wong et al provide evidence for a pathogenic mechanism in ICL -the potential contribution of autoantibodies against CD4 + T cells, which are capable of depleting these lymphocytes (14). Although ICL patients with opportunistic infections are likely to have more profound CD4 + T cell lymphopenia, those who have autoantibodies typically do not have inhibitor, has been approved by the United States Food and Drug Administration for patients with systemic lupus erythematosus (SLE) who have autoantibodies, and it has shown efficacy in reducing symptoms and leading to a modest decrease in autoantibodies (27).…”

“…In this issue of the JCI, Perez-Diez and Wong et al (14) implicate autoantibodies, some of which are specific for lymphocytes in a subset of adult ICL patients, as a possible pathogenic mechanism responsible for the reduction in circulating CD4 + T cells. The authors assessed the prevalence of autoantibodies in the sera from 51 adult ICL patients (out of a cohort of 72).…”

“…Deep immune profiling of T and B cell subsets (17,18) in ICL patients with and without autoantibodies, with and without opportunistic infection may allow us to correlate dysregulated subsets to observed phenotype(s) ( Figure 1B). Perez-Diez and Wong et al have already made a start in this direction with their autoantibody profiling (14). It will be important to uncover further details about the effector mechanisms of the autoantibodies discovered, including the inciting factors and outcomes of these antibodies binding their target epitopes on T cells and either inducing or blocking specific signaling cascades.…”

“…The cohort evaluated by Perez-Diez and Wong et al (14) includes only adults. The inclusion of infant and older children cohorts with ICL in future studies will allow for a comparison of the similarities and differences in the pathophysiology of this syndrome (19) and how it changes with age, including whether these patients develop autoantibodies as infants or young children.…”