T-cell abnormalities in common variable immunodeficiency
J S Jaffe1, E Eisenstein, M C Sneller
1Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Insights
Common variable immunodeficiency (CVI) involves distinct immune defects. Some CVI patients show T-cell defects in lymphokine production, while others have altered T-cell subsets that can suppress B-cell function.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Common variable immunodeficiency (CVI) is a complex disorder with diverse immunological abnormalities.
- Understanding the specific cellular and molecular defects in CVI is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the detailed immunologic defects in different patient groups within CVI.
- To characterize T-cell lymphokine production and identify specific cellular abnormalities in CVI.
Main Methods:
- Stimulation of T-cells with various activation stimuli, including phytohemagglutinin and CD3-T-cell receptor complex activation.
- Analysis of lymphokine (IL-2, IL-4, IL-5, interferon-gamma) mRNA and protein production.
- Flow cytometry to assess T-cell subsets (CD4/CD8 ratio, CD57 marker).
- Functional assays to evaluate T-cell suppression of B-cell immunoglobulin production.
Main Results:
- One CVI subgroup (approx. 60%) exhibits T-cells with reduced IL-2, IL-4, and IL-5 production, but normal interferon-gamma when IL-2 is present, suggesting a downstream defect in lymphokine gene activation.
- A second CVI subgroup (approx. 30%) presents with a reduced CD4/CD8 ratio and increased CD57+ CD8+ T-cells.
- In the second subgroup, CD8+ T-cells produce increased interferon-gamma and exhibit suppressor activity on IgG production by B-cells.
Conclusions:
- CVI is characterized by at least two distinct T-cell related immunologic defects.
- The findings highlight the heterogeneity of CVI and point to specific molecular and cellular pathways that are impaired.
- Further research into these defects may lead to targeted therapies for CVI patients.
Abstract:
Common variable immunodeficiency (CVI) is a heterogeneous condition marked by a number of different immunologic defects. One group of patients, perhaps 60% of the CVI group as a whole, is characterized by T cells that produce reduced amounts of IL-2 (mRNA and protein product), IL-4, and IL-5 (mRNA) when stimulated with phytohemagglutinin. This defect does not extend to all lymphokines, however, because the cells produce normal amounts of interferon-gamma (mRNA and protein product) when exogenous IL-2 is present. Recently, we have reexamined the T cell lymphokine production defect using a panoply of T-cell activation stimuli and have shown that the defect is a subtle one that depends on activation of the cell via the CD3-T-cell receptor complex. Because T cells proliferate normally when stimulated via this receptor, this finding suggests the presence of a "downstream" defect, perhaps one involving the factors that are necessary for activation of lymphokine genes. A second form of CVI, in this case involving approximately 30% of the CVI group as a whole, is characterized by a reduced CD4/CD8 ratio and elevated numbers of CD8+ T cells bearing the CD57 marker. Although the CD4+ T cells in this patient group elaborate normal amounts of IL-2 under various activation conditions, their CD8+ T cells produce increased amounts of interferon-gamma. Furthermore, the CD8+ T cells in this case act as "suppressor" T cells, which suppress IgG production but not IgM production of purified (normal) SAC+, IL-2-induced B cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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