Evaluation of the TLR negative regulatory network in CVID patients
Roozbeh Sanaei1, Nima Rezaei2,3,4, Asghar Aghamohammadi5,6
1Immunology Research Center (IRC), Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
Insights
Common variable immunodeficiency (CVID) patients show altered expression of Toll-like receptor (TLR) negative regulators. These molecular defects correlate with CVID complications, suggesting a role in disease pathogenesis.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Common variable immunodeficiency (CVID) is a primary immunodeficiency disease marked by hypogammaglobulinemia, leading to recurrent infections and complications.
- Recent studies indicate defects in Toll-like receptor (TLR) signaling pathways in CVID patients.
Purpose of the Study:
- To investigate the expression and activation status of negative regulatory molecules for TLR4 and TLR9 in CVID patients.
- To explore the correlation between these molecular defects and clinical manifestations of CVID.
Main Methods:
- Peripheral blood mononuclear cells (PBMCs) from CVID patients and healthy individuals were analyzed for SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts using TaqMan real-time PCR.
- TLR4 and TLR9 were activated using lipopolysaccharide (LPS) and CpG-oligodeoxynucleotide (CpG-ODN), respectively.
- Cytokine production (IFN-α and TNF-α) was measured via ELISA.
Main Results:
- CVID patients exhibited deficient IRAK-M and TNFAIP3 transcripts in unstimulated PBMCs and reduced TNF-α and IFN-α production post-activation.
- Abnormal upregulation of RFN216 and TNFAIP3 following TLR9 activation was observed in CVID patients compared to controls.
- Significant correlations were found between abnormal IRAK-M transcripts and lymphadenopathy, and between TNFAIP3 transcripts and inflammatory conditions.
Conclusions:
- The transcriptional regulation of negative immune modulators is disturbed in CVID patients.
- These molecular dysregulations may contribute to the pathogenesis of CVID and its associated complications, including autoimmunity and inflammation.
Abstract:
Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations. TLR4 and 9 were activated by lipopolysaccharide (LPS) and unmethylated CpG-oligodeoxynucleotide (CpG-ODN), respectively. Production of IFN-α and TNF-α cytokines, as a part of the functional response of mentioned TLRs, was also measured using ELISA. Deficient transcripts of IRAK-M and TNFAIP3 in unstimulated PBMCs and lower production of TNF-α and IFN-α after treatments were observed. Upregulation of RFN216 and TNFAIP3 after TLR9 activation was abnormal compared to healthy individuals. Significant correlations were found between abnormal IRAK-M and TNFAIP3 transcripts, and lymphadenopathy and inflammatory scenarios in patients, respectively. It seems that the transcriptional status of some negative regulatory molecules is disturbed in CVID patients, and this could be caused by the underlying pathogenesis of CVID and could involve complications like autoimmunity and inflammatory responses.
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