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T-cell activation discriminates subclasses of symptomatic primary humoral immunodeficiency diseases in adults.

Picat MQ, Thiébaut R, Lifermann F, Delbrel X, Adoue D, Wittkop L, Fauchais AL, Rispal P, Moreau JF, Viallard JF - BMC Immunol. (2014)

Bottom Line: Symptomatic Primary Humoral Immunodeficiency Diseases (PHID) constitute a highly heterogeneous group of diseases characterized by a shared hypogammaglobulinemia, resulting in increased risk of recurrent or severe infections.Combining the set of markers involved in PHID supported the existence of two distinct mechanisms associated with complications.These results highlight the importance of T-cell activation that may improve discrimination of PHID patients in specific subgroups and help to identify patients with different clinical outcomes.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux F-33076, France. rodolphe.thiebaut@isped.u-bordeaux2.fr.

ABSTRACT

Background: Symptomatic Primary Humoral Immunodeficiency Diseases (PHID) constitute a highly heterogeneous group of diseases characterized by a shared hypogammaglobulinemia, resulting in increased risk of recurrent or severe infections. Associations have been described with a variety of immunological abnormalities involving B and T-cell differentiation, T-cell activation and innate immunity. However, PHID discrimination remains based on B-lymphocyte abnormalities and other components of the immune system have not been sufficiently taken into account. We carried out unsupervised and supervised methods for classification in a cohort of 81 symptomatic PHID patients to evaluate the relative importance of 23 immunological parameters and to select relevant markers that may be useful for diagnosis and prognosis.

Results: We identified five groups of patients, among which the percentage of PHID complications varied substantially. Combining the set of markers involved in PHID supported the existence of two distinct mechanisms associated with complications. Switched memory B-cell attrition and CD8+ HLA-DR + activated T-cell increase were the prominent abnormalities observed in PHID complications. Furthermore, in a subgroup of 57 patients with common variable immunodeficiency, the classification that added CD8+ HLA-DR + to the consensual EUROclass classification was better than the EUROclass model in predicting complications.

Conclusion: These results highlight the importance of T-cell activation that may improve discrimination of PHID patients in specific subgroups and help to identify patients with different clinical outcomes.

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Related in: MedlinePlus

Immunological interpretation of 5 clusters of CVID plotted on the first two principal components. ALTADIH Cohort, 2007-2010. The percentage of CVID complications, noted next to the clusters, increased in a clockwise manner as phenotypes approach the projection of activated HLA-DR + markers plotted in Figure 1 (red arrow).
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Figure 3: Immunological interpretation of 5 clusters of CVID plotted on the first two principal components. ALTADIH Cohort, 2007-2010. The percentage of CVID complications, noted next to the clusters, increased in a clockwise manner as phenotypes approach the projection of activated HLA-DR + markers plotted in Figure 1 (red arrow).

Mentions: The projection of PHID patients, classified in the above 5 defined clusters, onto the plan spanned by the first two principal components led to define their immunological characteristics (Figure 3 that needs to be read in conjunction with Figure 1; Table 3). For example, patients plotted in the upper-left corner of Figure 3, mainly patients of cluster 4, are characterized by variables plotted in the same quadrant in Figure 1, in particular HLA-DR + markers. Thus, the 33 patients making up cluster 1 (23 CVID patients and 10 IgG SD patients) were characterized by normal innate and adaptive immunity. They were represented on the upper-right corner that grouped innate cells, CD19+ B-cells, CD19 + CD27 + IgD- switched memory B-cells, CD3+, CD4+, CD8+ T-cells, and regulatory T-cells (Figure 1). Cluster 2 (lower-right corner, Figure 3) represented 18 patients (8 CVID patients and 10 IgG SD patients) characterized by increased naïve CD8+ T-cells. Cluster 1 and cluster 2 looked similar and were combined in an up stream clustering. Cluster 3 (1 patient with Good’s syndrome and 3 CVID patients) and cluster 4 (8 CVID patients) were characterized by an increase of HLA-DR + activation, terminal effector CD8+ T cells and immunosenescence marker (Table 3). As expected, these patients were represented in the upper-left corner near CD3+, CD4+ and CD8+ T cells expressing HLA-DR+, CD45RA + CCR7- terminal effector CD8+ T cells, and the CD8 + CD57+ marker (Figure 1). In cluster 3, one CVID patient had been splenectomized before enrolment (in 2001). In this patient, splenectomy deeply affects the absolute numbers but not grossly the percentages of the lymphocyte subpopulations in the blood. In parallel, the patient with Good’s syndrome in cluster 3 was differently plotted, i.e. in the upper-right corner near CD8+, reflecting the high blood CD8+ T-cell absolute numbers known in Good’s syndrome. Cluster 5 (lower-left corner, Figure 3) consisted of 16 patients with B-cell deficiency (13 CVID, 1 IgG SD and 2 Good’s syndrome): the lower-left corner where no immunological parameters are plotted has to be interpreted as the symmetrical and diagonal opposite of the upper-right corner. Thus, the meaning of cluster 5 (lower-left corner, Figure 3) is a cluster gathering B-cell deficiencies because the patients are plotted on the opposite corner of the plot of CD19+, CD27 + IgD+, CD27 + IgD-, CD27-IgD- which all are markers plotted in the upper-right corner. Table 3 confirms the given interpretation of the clusters.


T-cell activation discriminates subclasses of symptomatic primary humoral immunodeficiency diseases in adults.

Picat MQ, Thiébaut R, Lifermann F, Delbrel X, Adoue D, Wittkop L, Fauchais AL, Rispal P, Moreau JF, Viallard JF - BMC Immunol. (2014)

Immunological interpretation of 5 clusters of CVID plotted on the first two principal components. ALTADIH Cohort, 2007-2010. The percentage of CVID complications, noted next to the clusters, increased in a clockwise manner as phenotypes approach the projection of activated HLA-DR + markers plotted in Figure 1 (red arrow).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008268&req=5

Figure 3: Immunological interpretation of 5 clusters of CVID plotted on the first two principal components. ALTADIH Cohort, 2007-2010. The percentage of CVID complications, noted next to the clusters, increased in a clockwise manner as phenotypes approach the projection of activated HLA-DR + markers plotted in Figure 1 (red arrow).
Mentions: The projection of PHID patients, classified in the above 5 defined clusters, onto the plan spanned by the first two principal components led to define their immunological characteristics (Figure 3 that needs to be read in conjunction with Figure 1; Table 3). For example, patients plotted in the upper-left corner of Figure 3, mainly patients of cluster 4, are characterized by variables plotted in the same quadrant in Figure 1, in particular HLA-DR + markers. Thus, the 33 patients making up cluster 1 (23 CVID patients and 10 IgG SD patients) were characterized by normal innate and adaptive immunity. They were represented on the upper-right corner that grouped innate cells, CD19+ B-cells, CD19 + CD27 + IgD- switched memory B-cells, CD3+, CD4+, CD8+ T-cells, and regulatory T-cells (Figure 1). Cluster 2 (lower-right corner, Figure 3) represented 18 patients (8 CVID patients and 10 IgG SD patients) characterized by increased naïve CD8+ T-cells. Cluster 1 and cluster 2 looked similar and were combined in an up stream clustering. Cluster 3 (1 patient with Good’s syndrome and 3 CVID patients) and cluster 4 (8 CVID patients) were characterized by an increase of HLA-DR + activation, terminal effector CD8+ T cells and immunosenescence marker (Table 3). As expected, these patients were represented in the upper-left corner near CD3+, CD4+ and CD8+ T cells expressing HLA-DR+, CD45RA + CCR7- terminal effector CD8+ T cells, and the CD8 + CD57+ marker (Figure 1). In cluster 3, one CVID patient had been splenectomized before enrolment (in 2001). In this patient, splenectomy deeply affects the absolute numbers but not grossly the percentages of the lymphocyte subpopulations in the blood. In parallel, the patient with Good’s syndrome in cluster 3 was differently plotted, i.e. in the upper-right corner near CD8+, reflecting the high blood CD8+ T-cell absolute numbers known in Good’s syndrome. Cluster 5 (lower-left corner, Figure 3) consisted of 16 patients with B-cell deficiency (13 CVID, 1 IgG SD and 2 Good’s syndrome): the lower-left corner where no immunological parameters are plotted has to be interpreted as the symmetrical and diagonal opposite of the upper-right corner. Thus, the meaning of cluster 5 (lower-left corner, Figure 3) is a cluster gathering B-cell deficiencies because the patients are plotted on the opposite corner of the plot of CD19+, CD27 + IgD+, CD27 + IgD-, CD27-IgD- which all are markers plotted in the upper-right corner. Table 3 confirms the given interpretation of the clusters.

Bottom Line: Symptomatic Primary Humoral Immunodeficiency Diseases (PHID) constitute a highly heterogeneous group of diseases characterized by a shared hypogammaglobulinemia, resulting in increased risk of recurrent or severe infections.Combining the set of markers involved in PHID supported the existence of two distinct mechanisms associated with complications.These results highlight the importance of T-cell activation that may improve discrimination of PHID patients in specific subgroups and help to identify patients with different clinical outcomes.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux F-33076, France. rodolphe.thiebaut@isped.u-bordeaux2.fr.

ABSTRACT

Background: Symptomatic Primary Humoral Immunodeficiency Diseases (PHID) constitute a highly heterogeneous group of diseases characterized by a shared hypogammaglobulinemia, resulting in increased risk of recurrent or severe infections. Associations have been described with a variety of immunological abnormalities involving B and T-cell differentiation, T-cell activation and innate immunity. However, PHID discrimination remains based on B-lymphocyte abnormalities and other components of the immune system have not been sufficiently taken into account. We carried out unsupervised and supervised methods for classification in a cohort of 81 symptomatic PHID patients to evaluate the relative importance of 23 immunological parameters and to select relevant markers that may be useful for diagnosis and prognosis.

Results: We identified five groups of patients, among which the percentage of PHID complications varied substantially. Combining the set of markers involved in PHID supported the existence of two distinct mechanisms associated with complications. Switched memory B-cell attrition and CD8+ HLA-DR + activated T-cell increase were the prominent abnormalities observed in PHID complications. Furthermore, in a subgroup of 57 patients with common variable immunodeficiency, the classification that added CD8+ HLA-DR + to the consensual EUROclass classification was better than the EUROclass model in predicting complications.

Conclusion: These results highlight the importance of T-cell activation that may improve discrimination of PHID patients in specific subgroups and help to identify patients with different clinical outcomes.

Show MeSH
Related in: MedlinePlus