Gene expression profiling in peripheral blood mononuclear cells of patients with common variable immunodeficiency: modulation of adaptive immune response following intravenous immunoglobulin therapy.
BACKGROUND
Regular intravenous immunoglobulin treatment is used to replace antibody deficiency in primary immunodeficiency diseases; however the therapeutic effect seems to be related not only to antibody replacement but also to an active role in the modulation of the immune response. Common variable immunodeficiency is the most frequent primary immunodeficiency seen in clinical practice.


METHODS
We have studied the effect of intravenous immunoglobulin replacement in patients with common variable immunodeficiency by evaluating the gene-expression profiles from Affimetrix HG-U133A. Some of the gene array results were validated by real time RT-PCR and by the measurement of circulating cytokines and chemokines by ELISA. Moreover we performed FACS analysis of blood mononuclear cells from the patients enrolled in the study.


RESULTS
A series of genes involved in innate and acquired immune responses were markedly up- or down-modulated before therapy. Such genes included CD14, CD36, LEPR, IRF-5, RGS-1, CD38, TNFRSF25, IL-4, CXCR4, CCR3, IL-8. Most of these modulated genes showed an expression similar to that of normal controls after immunoglobulin replacement. Real time RT-PCR of selected genes and serum levels of IL-4, CXCR4 before and after therapy changed accordingly to gene array results. Interestingly, serum levels of IL-8 remained unchanged, as the corresponding gene, before and after treatment. FACS analysis showed a marked decrease of CD8+T cells and an increase of CD4+T cells following treatment. Moreover we observed a marked increase of CD23⁻CD27⁻IgM⁻IgG⁻ B cells (centrocytes).


CONCLUSIONS
Our results are in accordance with previous reports and provide further support to the hypothesis that the benefits of intravenous immunoglobulin therapy are not only related to antibody replacement but also to its ability to modulate the immune response in common variable immunodeficiency.
Department of Immunology, Institute Giannina Gaslini, Genova, Italy.
Marzia
M
Dolcino
Department of Medicine, University of Verona, Verona, Italy.
Giuseppe
G
Patuzzo
Department of Medicine, University of Verona, Verona, Italy.
Alessandro
A
Barbieri
Department of Medicine, University of Verona, Verona, Italy.
Elisa
E
Tinazzi
Department of Medicine, University of Verona, Verona, Italy.
Monica
M
Rizzi
Department of Medicine, University of Verona, Verona, Italy.
Ruggero
R
Beri
Department of Medicine, University of Verona, Verona, Italy.
Giuseppe
G
Argentino
Department of Experimental Medicine, University of Genova, Genova, Italy.
Andrea
A
Ottria
Department of Medicine, University of Verona, Verona, Italy.
Claudio
C
Lunardi
Department of Immunology, Institute Giannina Gaslini, Genova, Italy; Department of Experimental Medicine, University of Genova, Genova, Italy.
Antonio
A
Puccetti
D056704:Adaptive Immunity; D000328:Adult; D002469:Cell Separation; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018075:RNA, Complementary / Q000378:metabolism
D016756:Immunoglobulins, Intravenous; D018075:RNA, Complementary